Substituted pyrazoles

ABSTRACT

Substituted pyrazoles, methods of manufacturing them, compositions containing them, and methods of using them to treat, for example, autoimmune diseases mediated by cathepsin S are described.

This application is a continuation of U.S. application Ser. No.09/927,324, filed Aug. 10, 2001, which claims benefit of U.S.Provisional Application Ser. No. 60/225,178, filed Aug. 14, 2000, whichare incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

This invention relates to a series of substituted pyrazoles,pharmaceutical compositions containing these compounds, andintermediates used in their manufacture, and methods of using them.

BACKGROUND OF THE INVENTION

Cathepsin S (EC 3.4.22.27) is a cysteine protease of the papain familyfound primarily in lysosomes (Bromme, D.; McGrath, M. E. High LevelExpression and Crystallization of Recombinant Human Cathepsin S. ProteinScience 1996, 5, 789-791).

The role of cathepsin S in the immune response is anticipated by itstissue distribution: cathepsin S is found primarily in lymphatictissues, lymph nodes, the spleen, B lymphocytes, and macrophages(Kirschke, H. Chapter 211. Cathepsin S. In Handbook of ProteolyticEnzymes. Barrett, A. J.; Rawlings, N. D.; Woessner, J. F., Eds. SanDiego: Academic Press, 1998. pp. 621-624.). Cathepsin S inhibitors havebeen shown in animal models to modulate antigen presentation and areeffective in an animal model of asthma (Riese, R. J.; Mitchell, R. N.;Villadangos, J. A.; Shi, G.-P.; Palmer, J. T.; Karp, E. R.; De Sanctis,G. T.; Ploegh, H. L.; Chapman, H. A. Cathepsin S Activity RegulatesAntigen Presentation and Immunity. J. Clin. Invest. 1998, 101, 2351-2363and Shi, G.-P.; Villadangos, J. A.; Dranoff, G.; Small, C.; Gu, L.;Haley, K. J.; Riese, R.; Ploegh, H. L.; Chapman, H. A. Cathepsin SRequired for Normal MHC Class II Peptide Loading and Germinal CenterDevelopment. Immunity 1999, 10,197-206.).

Mice in which the gene encoding cathepsin S has been knocked out areless susceptible to collagen-induced arthritis and their immune systemshave an impaired ability to respond to antigens (Nakagawa, T. Y.;Brissette, W. H.; Lira, P. D.; Griffiths, R. J.; Petrushova, N.; Stock,J.; McNeish, J. D.; Eastman, S. E.; Howard, E. D.; Clarke, S. R. M.;Rosloniec, E. F.; Elliott, E. A.; Rudensky, A. Y. Impaired InvariantChain Degradation and Antigen Presentation and DiminishedCollagen-Induced Arthritis in Cathepsin S Null Mice. Immunity 1999, 10,207-217).

These data demonstrate that compounds that inhibit the proteolyticactivity of human cathepsin S should find utility in the treatment ofchronic autoimmune diseases including, but not limited to, lupus,rheumatoid arthritis, and asthma; and have potential utility inmodulating the immune response to tissue transplantation.

There are a number of cathepsin S inhibitors reported in the literature.The most important patents are listed below.

Certain dipeptidyl nitrites are claimed by Novartis as cathepsin Sinhibitors in: Altmann, et. al. WO-99/24460.

Dipeptidyl vinyl sulfones are claimed by Arris (now Axys) as cysteineprotease (including cathepsin S) inhibitors in: Palmer, et. al. U.S.Pat. No. 5,976,858.

Certain peptidyl sulfonamides are claimed by Arris/Axys as cysteineprotease (including cathepsin S) inhibitors in: Palmer, et. al. U.S.Pat. No. 5,776,718 (assigned to Arris, now Axys) & Klaus, et. al. U.S.Pat. No. 6,030,946 (assigned to Axys).

Compounds somewhat similar to those of the present invention aredescribed in the following references.

Winters, et. al. (Winters, G.; Sala, A.; Barone, D.; Baldoli, E. J. Med.Chem. 1985, 28, 934-940; Singh, P.; Sharma, R. C. Quant. Struct.-Act.Relat. 1990, 9, 29-32; Winters, G.; Sala, A.; Barone, D. in U.S. Pat.No. 4,500,525 (1985)) have described bicyclic pyrazoles of the typeshown below. R never contains a heterocyclic ring and no proteaseinhibitor activity is ascribed to these molecules; they are described asα1-adrenergic receptor modulators.

Shutske, et. al. claim the bicylic pyrazoles below. The pyridine ring isaromatic in their system (Shutske, G. M.; Kapples, K. J.; Tomer, J. D.U.S. Pat. No. 5,264,576 (1993)). Although reference is made to R being alinker to a heterocycle, the claims specify only R=hydrogen. Thecompounds are referred to as serotonin reuptake inhibitors.

The compound2-[4-[4-(3-methyl-5-phenyl-1H-pyrazol-1-yl)butyl]-1-piperazinyl]-pyrimidineis known from EP-382637, which describes pyrimidines having anxiolyticproperties. This compound and analogs are further described in EP-502786as cardiovascular and central nervous system agents. Pharmaceuticalformulations with such compounds are disclosed in EP-655248 for use inthe treatment of gastric secreation and as anti-ulcer agents. WO-9721439describes medicaments with such compounds for treatingobsessive-compulsive disorders, sleep apnea, sexual dysfunctions, emesisand motion sickness.

The compounds5-methyl-3-phenyl-1-[4-(4-phenyl-1-piperazinyl)butyl]-1H-indazole and5-bromo-3-(2-chlorophenyl)-1-[4-(4-phenyl-1-piperazinyl)butyl]-1H-indazole,in particular the hydrochloride salts thereof, are known from WO-9852940and CA 122:314528, where these and similar compounds are described askinase inhibitors in the former reference and possessing affinity forbenzodiazepine receptors in the latter reference.

SUMMARY OF THE INVENTION

The present invention concerns compounds which can be represented byformula (I):

wherein:

-   -   Ar₂ is a monocyclic or bicyclic ring system, unsaturated,        saturated or aromatic, optionally fused, optionally including        between 1 and 5 heteroatom ring moieties independently selected        from O, S, N, SO₂, and C═O; said Ar₂ ring system being        optionally substituted with between 1 and 4 substituents;    -   R⁵ and R⁶ are independently selected from hydrogen and        C₁₋₅alkyl;    -   R⁷ and R⁸ are independently hydrogen, C₁₋₅ alkyl, C₂₋₅ alkenyl,        C₁₋₅ alkoxy, C₁₋₅ alkylthio, halogen, or a 4-7 membered        carbocyclyl or heterocyclyl;    -   alternatively, R⁷ and R⁸ can be taken together to form an        optionally substituted 5- to 7-membered carbocyclic or        heterocyclic ring, which ring may be unsaturated or aromatic,        and may be optionally substituted with between one and three        substituents independently selected from halo, cyano, amino,        hydroxy, nitro, R⁴, R⁴O—, R⁴S—, R⁴O(C₁₋₅ alkylene)-, R⁴O(C═O)—,        R⁴(C═O)—, R⁴(C═S)—, R⁴(C═O)O—, R⁴O(C═O)(C═O)—, R⁴SO₂, NHR⁴⁴SO₂—,        and NHR⁴⁴(C═O)—;    -   R⁴ is H, C₁₋₅ alkyl, C₂₋₅ alkenyl, C₁₋₅ heterocyclyl, (C₁₋₅        heterocyclyl)C₁₋₆ alkylene, phenyl, benzyl, phenethyl, NH₂,        mono- or di(C₁₋₆ alkyl)N—, or R⁴²OR⁴³—, wherein R⁴² is H, C₁₋₅        alkyl, C₂₋₅ alkenyl, phenyl, benzyl, phenethyl, C₁₋₅        heterocyclyl, or (C₁₋₅ heterocyclyl)C₁₋₆ alkylene and R⁴³ is        C₁₋₅ alkylene, phenylene, or divalent C₁₋₅ heterocyclyl;    -   R⁴⁴ is one of the values for R⁴;    -   n is 0, 1, or 2;    -   G is C₃₋₆ alkenediyl or C₃₋₆ alkanediyl, optionally substituted        with hydroxy, halogen, C₁₋₅ alkoxy, C₁₋₅ alkyl, oxo,        hydroximino, CO₂R^(k), R^(k)R^(l)N, R^(k)R^(l)NCO₂, (L)-C₁₋₄        alkylene-, (L)-C₁₋₅ alkoxy, N₃ or [(L)-C₁₋₅ alkylene]amino;    -   each of R^(k) and R^(l) is independently hydrogen, C₁₋₅ alkyl,        C₃₋₅ alkenyl, phenyl, benzyl, phenethyl, or C₁₋₅ heterocyclyl;        alternatively R^(k) and R^(l), can be taken together to form an        optionally substituted 4- to 7-membered heterocyclic ring, which        ring may be saturated, unsaturated or aromatic;    -   L is amino, mono- or di-C₁₋₅ alkylamino, pyrrolidinyl,        morpholinyl, piperidinyl homopiperidinyl, or piperazinyl,        wherein available ring nitrogens may be optionally substituted        with C₁₋₅ alkyl, benzyl, C₂₋₅ acyl, C₁₋₅ alkylsulfonyl, or C₁₋₅        alkoxycarbonyl;    -   Ar represents a monocyclic or bicyclic aryl or heteroaryl ring,        optionally substituted with between 1 and 3 substituents        independently selected from halogen, C₁₋₅ alkoxy, C₁₋₅ alkyl,        C₂₋₅ alkenyl, cyano, nitro, R²²R²³N, R²⁴SO₂, R²⁴S, R²⁴SO,        R²⁴OC═O, R²²R²³NC═O, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy, C₁₋₅        haloalkylthio, and C₁₋₅ alkylthio;    -   R²² is hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, phenethyl,        benzyl, or C₁₋₅ heterocyclyl, C₂₋₈ acyl, aroyl, R³⁸OC═O,        R²⁵R²⁶NC═O, R³⁸SO, R³⁸S₂, R³⁸S, or R²⁵R²⁶NSO₂;    -   R³⁸ is H, C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, benzyl, phenethyl or        C₁₋₅ heterocyclyl;    -   R²³ is hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, benzyl or        C₁₋₅ heterocyclyl; alternatively, R²² and R²³ can be taken        together to form an optionally substituted 4- to 7-membered        heterocyclic ring, which ring may be saturated, unsaturated or        aromatic;    -   R²⁴ is C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, benzyl, or C₁₋₅        heterocyclyl;    -   R²⁵ and R²⁶ independently are hydrogen, C₁₋₅ alkyl, C₃₋₅        alkenyl, phenyl, benzyl, or C₁₋₅ heterocyclyl;    -   or, alternatively, R²⁵ and R²⁶ can be taken together to form an        optionally substituted 4- to 7-membered heterocyclic ring, which        ring may be saturated, unsaturated or aromatic;    -   W represents O, S, NR²⁷, C═O, (C═O)NH, NH(C═O), CHR²⁸, or a        covalent bond;    -   R^(z) is H or OH and the dashed line is absent; or R^(z) is        absent where the dashed line is an SP² bond;    -   R²⁷ is hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, naphthyl,        benzyl, phenethyl, C₁₋₅ heterocyclyl, C₂₋₈ acyl, aroyl, R²⁹OC═O,        R³⁰R³¹NC═O, R²⁹SO, R²⁹S, R²⁹SO₂, or R³⁰R³¹NSO₂;    -   or, alternatively, R²⁷ and part of Ar₂ can be taken together to        form an optionally substituted 5- or 6-membered heterocyclic        ring with optionally 1 to 3 additional heteroatom moieties in        the ring selected from O, NR⁹, NR¹⁰, N, SO₂, C═O, and S; which        ring may be saturated, unsaturated or aromatic; R⁹ and R¹⁰ are        independently selected from H, C₁₋₃ alkyl, and —CH₂CO₂(C₁₋₄        alkyl);    -   R²⁸ is hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl, hydroxy, phenyl,        benzyl, C₁₋₅ heterocyclyl, R²⁹O, R³⁰R³¹NC═O, R²⁹S, R²⁹SO,        R²⁹SO₂, or R³⁰R³¹ NSO₂;    -   R²⁹ is C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, benzyl, or C₁₋₅        heterocyclyl;    -   R³⁰ and R³¹ are independently selected from hydrogen, C₁₋₅        alkyl, C₃₋₅ alkenyl, phenyl, benzyl, phenethyl, naphthyl, and        C₁₋₅ heteroaryl; alternatively, R³⁰ and R³¹ can be taken        together to form an optionally substituted 4- to 7-membered ring        carbocyclic or heterocyclic ring, which ring may be saturated,        unsaturated or aromatic;    -   wherein each of the above hydrocarbyl or heterocarbyl groups,        unless otherwise indicated, and in addition to any specified        substituents, is optionally and independently substituted with        between 1 and 3 substituents selected from methyl, halomethyl,        hydroxymethyl, halo, hydroxy, amino, nitro, cyano, C₁₋₅ alkyl,        C₁₋₅ alkoxy, —COOH, C₂₋₆ acyl, [di(C₁₋₄ alkyl)amino]C₂₋₅        alkylene, [di(C₁₋₄ alkyl)amino] C₂₋₅ alkyl-NH—CO—, and C₁₋₅        haloalkoxy;    -   or a pharmaceutically acceptable salt, amide, or ester thereof;        or a stereoisomeric form thereof.

One embodiment of the invention is a compound of formula(I), wherein Ar₂is selected from 5-7 membered monocyclic rings, and [5,6], [6,6], [6,5],and [5,5] fused bicyclic ring systems, said ring or ring system beingcarbocyclic or heterocyclic, saturated, unsaturated, or aromatic,optionally substituted with halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄hydroxyalkyl, nitro, hydroxy, amino, mono- or di-(C₁₋₆ alkyl)amino, C₁₋₄alkoxy, C₂₋₄ alkoxycarbonyl, C₂₋₆ acyl, C₂₋₆ acyloxy, C₁₋₅alkylsulfonyl, C₁₋₅ alkoxycarbonylc 1-4 alkoxy, cyano, and mono- ordi-(C₁₋₆ alkyl)carbamoyl.

Another embodiment of the invention is a compound of formula (I),wherein Ar₂ is selected from 2,5-di(C₁₋₆ alkyl)aminopyrrolyl and thefollowing 6 formulae:

wherein

-   -   each dashed line may be an sp² bond or absent;    -   X_(c) is O, S, or N; and X_(d) is O or S;    -   R¹ is hydrogen, halogen, C₁₋₅ alkoxy, hydroxy, C₁₋₅ alkyl, C₂₋₅        alkenyl, cyano, nitro, R^(a)R^(b)N, C₂₋₈ acyl, C₁₋₅        heterocyclyl, (C₁₋₅ heterocyclyl)C₁₋₅ alkylene, R¹¹S, R¹¹SO,        R¹¹SO₂, R^(c)OC═O, R^(c)R^(d)NC═O, or R^(c)R^(d)NSO₂; or R¹ can        be taken together with R²⁷ as provided below;    -   R² is hydrogen, halogen, C₁₋₅ alkoxy, hydroxy, C₁₋₅ alkyl, C₂₋₅        alkenyl, cyano, nitro, R^(e)R^(f)N, C₁₋₅ heterocyclyl, or C₂₋₈        acyl;    -   R³ is hydrogen, halogen, C₁₋₅ alkoxy, hydroxy, C₁₋₅ alkyl, C₂₋₅        alkenyl, cyano, nitro, R^(g)R^(h)N, C₂₋₈ acyl, C₁₋₅        heterocyclyl, R^(h)OC═O, R^(g)R^(h)NC═O, or R^(g)R^(h)NSO₂;    -   R^(a) is selected from hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl,        phenyl, benzyl, phenethyl, C₁₋₅ heterocyclyl, C₂₋₈ acyl, aroyl,        R^(j)OC═O, R^(i)R^(j)NC═O, R¹²SO, R¹²SO₂, R¹²S, and        R^(i)R^(j)NSO₂;    -   R^(e) is selected from hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl,        phenyl, benzyl, phenethyl, C₁₋₅ heterocyclyl, C₂₋₈ acyl, aroyl,        R³²OC═O, R³²R³³NC═O, R¹³SO, R¹³SO₂, R¹³S, and R³²R³³NSO₂;    -   R^(m) is selected from hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl,        phenyl, benzyl, phenethyl, C₁₋₅ heterocyclyl, C₂₋₈ acyl, aroyl,        R³⁴OC═O, R³⁴R³⁵NC═O, R¹⁵SO, R¹⁵SO₂, R¹⁵S, and R³⁴R³⁵NSO₂;    -   R^(o) is selected from hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl,        phenyl, benzyl, phenethyl, C₁₋₅ heterocyclyl, C₂₋₈ acyl, aroyl,        R³⁶OC═O, R³⁶R³⁷NC═O, R¹⁹SO, R¹⁹SO₂, R¹⁹S, and R³⁶R³⁷NSO₂;    -   each of R^(b), R^(f), R^(n), R^(p), R³², R³³, R³⁴, R³⁵, R³⁶,        R³⁷, R³⁹, and R⁴⁰ is independently selected from hydrogen, C₁₋₅        alkyl, C₃₋₅ alkenyl, phenyl, benzyl, phenethyl, and C₁₋₅        heteroaryl;    -   alternatively, R^(a) and R^(b), R^(e) and R^(f), R^(m) and        R^(n), and R^(o) and R^(p), independently, can be taken together        to form an optionally substituted 4- to 7-membered heterocyclic        ring, which ring may be saturated, unsaturated or aromatic;    -   each of R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁹, R³⁸, and R⁴¹ is        independently C₁₋₅ alkyl,    -   C₃₋₅ alkenyl, phenyl, benzyl, phenethyl, or C₁₋₅ heterocyclyl;        each of R^(c) and R^(d), and R^(i) and R^(j) are independently        are hydrogen, C₁₋₅ alkyl,

C₃₋₅ alkenyl, phenyl, benzyl, phenethyl, or C₁₋₅ heteroaryl;alternatively, R^(c) and R^(d), and R^(i) and R^(j), independently, canbe taken together to form an optionally substituted 4- to 7-memberedheterocyclic ring, which ring may be saturated, unsaturated or aromatic;

-   -   R⁹ is hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, benzyl,        phenethyl, C₁₋₅ heterocyclyl, C₂₋₈ acyl, aroyl, R¹⁷OC═O,        R¹⁷R¹⁸NC═O, R¹⁶S, R¹⁶SO, R¹⁶SO₂, or R¹⁷R¹⁸NSO₂;    -   R^(h) is hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, benzyl,        phenethyl or C₁₋₅ heterocyclyl; alternatively, R⁹ and R^(h) can        be taken together to form an optionally substituted 4- to        7-membered heterocyclic ring, which ring may be saturated,        unsaturated or aromatic;    -   R¹⁷ and R¹⁸ independently are hydrogen, C₁₋₅ alkyl, C₃₋₅        alkenyl, phenyl, benzyl, or C₁₋₅ heterocyclyl;    -   alternatively, R¹⁷ and R¹⁸ can be taken together to form an        optionally substituted 4- to 7-membered heterocyclic ring, which        ring may be saturated, unsaturated or aromatic;    -   Y^(e) is nitrogen or R²⁰C;    -   Z^(e) is nitrogen or R²¹C    -   R²⁰ is hydrogen, halogen, C₁₋₅ alkoxy, C₁₋₅ alkyl, C₂₋₅ alkenyl,        cyano, nitro, R^(m)R^(n)N, C₂₋₈ acyl, R^(m)OC═O, R¹⁴S, R¹⁴SO, or        R¹⁴SO₂;    -   R²¹ is hydrogen, halogen, C₁₋₅ alkoxy, C₁₋₅ alkyl, C₂₋₅ alkenyl,        cyano, nitro, R^(o)R^(p)N, C₂₋₈ acyl, R¹⁶OC═O, R¹¹S, R¹¹SO, or        R¹¹SO₂;    -   alternatively, R³ and R²⁰ or R³ and R²¹ can be taken together to        form an optionally substituted 5- or 6-membered carbocyclic or        heterocyclic ring, which ring may be saturated, unsaturated or        aromatic; wherein said ring may be optionally substituted with        halo, di(C₁₋₅ alkyl)amino, C₂₋₅ acyl, and C₁₋₅ alkoxy;    -   R²⁷ is hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, naphthyl,        benzyl, phenethyl,    -   C₁₋₅ heterocyclyl, C₂₋₈ acyl, aroyl, R²⁹OC═O, R³⁰R³¹NC═O, R²⁹SO,        R²⁹S, R²⁹ S or R³⁰R³¹NSO₂;    -   or, alternatively, R²⁷ and R¹ can be taken together to form an        optionally substituted 5- or 6-membered heterocyclic ring with        optionally 1 to 3 additional heteroatom moieties in the ring        selected from O, NR⁹, NR¹⁰, N, SO₂, C═O, and S; which ring may        be saturated, unsaturated or aromatic;    -   R⁹and R¹⁰ are independently selected from H, C₁₋₃ alkyl, and        —CH₂CO₂(C₁₋₄ alkyl);    -   X_(f) is CHR^(1f), ═N—, NH, C═O, SO₂, CHSR^(1f) wherein, in        formula (f), R^(1f) is hydrogen, halogen, C₁₋₅ alkoxy, hydroxy,        C₁₋₅ alkyl, C₃₋₅ alkenyl, cyano, nitro, R³⁹R⁴⁰N, C₂₋₈ acyl, C₁₋₅        heterocyclyl, (C₁₋₅ heterocyclyl)C₁₋₅ alkylene, R⁴¹S, R⁴¹SO,        R⁴¹SO₂, R³⁹OC═O, R³⁹R⁴⁰NC═O, R³⁹R⁴⁰NSO₂, R⁴¹SO₃—or R³⁹ (C═O)O—;    -   Y_(f) is CH₂, CHR^(2f), ═CR^(2f), O, or NR^(2f), wherein R^(2f)        is H, C₁₋₅ alkyl, C₃₋₅ alkenyl, C₂₋₈ acyl, C₁₋₅ heterocyclyl,        (C₁₋₅ heterocyclyl)-C₁₋₅ alkylene, C₁₋₅ haloalkyl, C₁₋₅        cyanoalkyl, (C₁₋₅ alkoxycarbonyl)C₁₋₅ alkylene, and        (phenylcarbonyl)NH—;    -   m is 0 or 1;    -   p is 0 or 1;    -   wherein each of the above hydrocarbyl or heterocarbyl groups,        unless otherwise indicated, and in addition to any specified        substituents, is optionally and independently substituted with        between 1 and 3 substituents selected from methyl, halomethyl,        hydroxymethyl, halo, hydroxy, amino, nitro, cyano, C₁₋₅ alkyl,        C₁₋₅ alkoxy, —COOH, C₂₋₆ acyl, [di(C₁₋₄ alkyl)amino]C₂₋₅        alkylene, [di(C₁₋₄ alkyl)amino] C₂₋₅ alkyl-NH—CO—, and C₁₋₅        haloalkoxy.

The disclosed compounds are high-affinity inhibitors of the proteolyticactivity of human cathepsin S. For use in medicine, the preparation ofpharmaceutically acceptable salts of compounds of formula (I) may bedesirable.

Certain compounds of the present invention may have one stereogenic atomand may exist as two enantiomers. Certain compounds of the presentinvention may have two or more stereogenic atoms and may further existas diastereomers. It is to be understood by those skilled in the artthat all such stereoisomers and mixtures thereof in any proportion areencompassed within the scope of the present invention.

Another aspect of the invention provides pharmaceutical compositionscomprising a compound of formula (I) and a pharmaceutically acceptablecarrier. A further embodiment of the invention is a process for making apharmaceutical composition comprising mixing a disclosed compound asdescribed above, with a suitable pharmaceutically acceptable carrier.

The invention also contemplates pharmaceutical compositions comprisingmore than one compound of formula (I) and compositions comprising acompound of formula (I) and another pharmaceutically active agent.

The invention features a method of treating disorders or conditionsmediated by the cathepsin S enzyme, in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of any of the compounds or pharmaceutical compositions describedabove. If more than one active agent is administered, thetherapeutically effective amount may be a jointly effective amount. Thecompounds described herein inhibit the protease activity of humancathepsin S, an enzyme involved in the immune response. In preferredembodiments, cathepsin S inhibition is selective. As such, the disclosedcompounds and compositions are useful in the prevention, inhibition, ortreatment of autoimmune diseases such as lupus, rheumatoid arthritis,and asthma, and for the prevention, inhibition, or treatment of tissuetransplant rejection.

Additional features and advantages of the invention will become apparentfrom the detailed description below, including examples, and theappended claims.

DETAILED DESCRIPTION OF THE INVENTION

The invention features pyrazole compounds of formula (I), methods ofmaking them, compositions containing them, and methods of using them totreat diseases and conditions, including those mediated by Cathepsin S.

A. TERMS

The following terms are defined below and by their usage throughout thisdisclosure.

“Alkyl” includes optionally substituted straight chain and branchedhydrocarbons with at least one hydrogen removed to form a radical group.Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl,t-butyl, 1-methylpropyl, pentyl, isopentyl, sec-pentyl, hexyl, heptyl,octyl, and so on. Alkyl includes cycloalkyl, such as cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl.

-   -   “Alkenyl” includes optionally substituted straight chain and        branched hydrocarbon radicals as above with at least one        carbon-carbon double bond (sp²). Alkenyls include ethenyl (or        vinyl), prop-1-enyl, prop-2-enyl (or allyl), isopropenyl (or        1-methylvinyl), but-1-enyl, but-2-enyl, butadienyls, pentenyls,        hexa-2,4-dienyl, and so on. Hydrocarbon radicals having a        mixture of double bonds and triple bonds, such as        2-penten-4-ynyl, are grouped as alkynyls herein. Alkenyl        includes cycloalkenyl. Cis and trans or (E) and (Z) forms are        included within the invention.

“Alkynyl” includes optionally substituted straight chain and branchedhydrocarbon radicals as above with at least one carbon-carbon triplebond (sp). Alkynyls include ethynyl, propynyls, butynyls, and pentynyls.Hydrocarbon radicals having a mixture of double bonds and triple bonds,such as 2-penten-4-ynyl, are grouped as alkynyls herein. Alkynyl doesnot include cycloalkynyl.

“Alkoxy” includes an optionally substituted straight chain or branchedalkyl group with a terminal oxygen linking the alkyl group to the restof the molecule. Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy,butoxy, t-butoxy, pentoxy and so on. “Aminoalkyl”, “thioalkyl”, and“sulfonylalkyl” are analogous to alkoxy, replacing the terminal oxygenatom of alkoxy with, respectively, NH (or NR), S, and SO₂. Heteroalkylincludes alkoxy, aminoalkyl, thioalkyl, and so on.

“Aryl” includes phenyl, naphthyl, biphenylyl, tetrahydronaphthyl, and soon, any of which may be optionally substituted. Aryl also includesarylalkyl groups such as benzyl, phenethyl, and phenylpropyl. Arylincludes a ring system containing an optionally substituted 6-memberedcarbocyclic aromatic ring, said system may be bicyclic, bridge, and/orfused. The system may include rings that are aromatic, or partially orcompletely saturated. Examples of ring systems include indenyl,pentalenyl, 1-4-dihydronaphthyl, indanyl, benzimidazolyl,benzothiophenyl, indolyl, benzofuranyl, isoquinolinyl, and so on.

“Heterocyclyl” includes optionally substituted aromatic and nonaromaticrings having carbon atoms and at least one heteroatom (O, S, N) orheteroatom moiety (SO₂, CO, CONH, COO) in the ring. Unless otherwiseindicated, a heterocyclic radical may have a valence connecting it tothe rest of the molecule through a carbon atom, such as 3-furyl or2-imidazolyl, or through a heteroatom, such as N-piperidyl or1-pyrazolyl. Preferably a monocyclic heterocyclyl has between 4 and 7ring atoms, or between 5 and 6 ring atoms; there may be between 1 and 5heteroatoms or heteroatom moieties in the ring, and preferably between 1and 3. A heterocyclyl may be saturated, unsaturated, aromatic (e.g.,heteroaryl), nonaromatic, or fused.

Heterocyclyl also includes fused, e.g., bicyclic, rings, such as thoseoptionally condensed with an optionally substituted carbocyclic orheterocyclic five- or six-membered aromatic ring. For example,“heteroaryl” includes an optionally substituted six-memberedheteroaromatic ring containing 1, 2 or 3 nitrogen atoms condensed withan optionally substituted five- or six-membered carbocyclic orheterocyclic aromatic ring. Said heterocyclic five- or six-memberedaromatic ring condensed with the said five- or six-membered aromaticring may contain 1, 2 or 3 nitrogen atoms where it is a six-memberedring, or 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfurwhere it is a five-membered ring.

Examples of heterocyclyls include thiazoylyl, furyl, pyranyl,isobenzofuranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl,isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl,isoindolyl, indolyl, indazolyl, purinyl, quinolyl, furazanyl,pyrrolidinyl, pyrrolinyl, imdazolidinyl, imidazolinyl, pyrazolidinyl,pyrazolinyl, piperidyl, piperazinyl, indolinyl, and morpholinyl. Forexample, preferred heterocyclyls or heterocyclic radicals includemorpholinyl, piperazinyl, pyrrolidinyl, pyridyl, cyclohexylimino,cycloheptylimino, and more preferably, piperidyl.

Examples illustrating heteroaryl are thienyl, furanyl, pyrrolyl,imidazolyl, oxazolyl, thiazolyl, benzothienyl, benzofuranyl,benzimidazolyl, benzoxazolyl, benzothiazolyl.

“Acyl” refers to a carbonyl moiety attached to either a hydrogen atom(i.e., a formyl group) or to an optionally substituted alkyl or alkenylchain, or heterocyclyl.

“Halo” or “halogen” includes fluoro, chloro, bromo, and iodo, andpreferably chloro or bromo as a substituent.

“Alkanediyl” or “alkylene” represents straight or branched chainoptionally substituted bivalent alkane radicals such as, for example,methylene, ethylene, propylene, butylene, pentylene or hexylene.

“Alkenediyl” represents, analogous to the above, straight or branchedchain optionally substituted bivalent alkene radicals such as, forexample, propenylene, butenylene, pentenylene or hexenylene. In suchradicals, the carbon atom linking a nitrogen preferably should not beunsaturated.

“Aroyl” refers to a carbonyl moiety attached to an optionallysubstituted aryl or heteroaryl group, wherein aryl and heteroaryl havethe definitions provided above. In particular, benzoyl isphenylcarbonyl.

As defined herein, two radicals, together with the atom(s) to which theyare attached may form an optionally substituted 4- to 7-, 5- to 7-, or a5- to 6-membered ring carbocyclic or heterocyclic ring, which ring maybe saturated, unsaturated or aromatic. Said rings may be as definedabove in the Summary of the Invention section. Particular examples ofsuch rings are as follows in the next section.

“Pharmaceutically acceptable salts, esters, and amides” includecarboxylate salts (e.g., C₁₋₈ alkyl, cycloalkyl, aryl, heteroaryl, ornon-aromatic heterocyclic) amino acid addition salts, esters, and amideswhich are within a reasonable benefit/risk ratio, pharmacologicallyeffective and suitable for contact with the tissues of patients withoutundue toxicity, irritation, or allergic response. Representative saltsinclude hydrobromide, hydrochloride, sulfate, bisulfate, nitrate,acetate, oxalate, valerate, oleate, palmitate, stearate, laurate,borate, benzoate, lactate, phosphate, tosylate, citrate, maleate,fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate,lactiobionate, and laurylsulfonate. These may include alkali metal andalkali earth cations such as sodium, potassium, calcium, and magnesium,as well as non-toxic ammonium, quaternary ammonium, and amine cationssuch as tetramethyl ammonium, methylamine, trimethylamine, andethylamine. See example, S. M. Berge, et al., “Pharmaceutical Salts,” J.Pharm. Sci., 1977, 66:1-19 which is incorporated herein by reference.Representative pharmaceutically acceptable amides of the inventioninclude those derived from ammonia, primary C₁₋₆ alkyl amines andsecondary di (C₁₋₆ alkyl) amines. Secondary amines include 5- or6-membered heterocyclic or heteroaromatic ring moieties containing atleast one nitrogen atom and optionally between 1 and 2 additionalheteroatoms. Preferred amides are derived from ammonia, C₁₋₃ alkylprimary amines, and di (C₁₋₂ alkyl)amines. Representativepharmaceutically acceptable esters of the invention include C₁₋₇ alkyl,C₅₋₇cycloalkyl, phenyl, and phenyl(C₁₋₆)alkyl esters. Preferred estersinclude methyl esters.

“Patient” or “subject” includes mammals such as humans and animals(dogs, cats, horses, rats, rabbits, mice, non-human primates) in need ofobservation, experiment, treatment or prevention in connection with therelevant disease or condition. Preferably, the patient or subject is ahuman.

“Composition” includes a product comprising the specified ingredients inthe specified amounts as well as any product which results directly orindirectly from combinations of the specified ingredients in thespecified amounts.

“Therapeutically effective amount” or “effective amount” means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.

Concerning the various radicals in this disclosure and in the claims,three general remarks are made. The first remark concerns valency. Aswith all hydrocarbon radicals, whether saturated, unsaturated oraromatic, and whether or not cyclic, straight chain, or branched, andalso similarly with all heterocyclic radicals, each radical includessubstituted radicals of that type and monovalent, bivalent, andmultivalent radicals as indicated by the context of the claims. Thecontext will indicate that the substituent is an alkylene or hydrocarbonradical with at least two hydrogen atoms removed (bivalent) or morehydrogen atoms removed (multivalent). An example of a bivalent radicallinking two parts of the molecule is G in formula (I) which links tworings.

Second, radicals or structure fragments as defined herein are understoodto include substituted radicals or structure fragments. Hydrocarbylsinclude monovalent radicals containing carbon and hydrogen such asalkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl (whether aromaticor unsaturated), as well as corresponding divalent radicals such asalkylene, alkenylene, phenylene, and so on. Heterocarbyls includemonovalent and divalent radicals containing carbon, hydrogen, and atleast one heteroatom. Examples of monovalent heterocarbyls include acyl,acyloxy, alkoxyacyl, heterocyclyl, heteroaryl, aroyl, benzoyl,dialkylamino, hydroxyalkyl, and so on.

Using “alkyl” as an example, “alkyl” should be understood to includesubstituted alkyl having one or more substitutions, such as between 1and 5, 1 and 3, or 2 and 4 substituents. The substituents may be thesame (dihydroxy, dimethyl), similar (chlorofluoro), or different(chlorobenzyl- or aminomethyl-substituted). Examples of substitutedalkyl include haloalkyl (such as fluoromethyl, chloromethyl,difluoromethyl, perchloromethyl, 2-bromoethyl, perfluoromethyl, and3-iodocyclopentyl), hydroxyalkyl (such as hydroxymethyl, hydroxyethyl,2-hydroxypropyl, aminoalkyl (such as aminomethyl, 2-aminoethyl,3-aminopropyl, and 2-aminopropyl), nitroalkyl, alkylalkyl, and so on. Adi(C₁₋₆ alkyl)amino group includes independently selected alkyl groups,to form, for example, methylpropylamino and isopropylmethylamino, inaddition dialkylamino groups having two of the same alkyl-group such asdimethyl amino or diethylamino.

Third, only stable compounds are intended. For example, where there isan NR′R″ group, and R can be an alkenyl group, the double bond is atleast one carbon removed from the nitrogen to avoid enamine formation.Similarly, where a dashed line is an optional sp² bond, if it is absent,the appropriate hydrogen atom(s) is(are) included.

Preferred substitutions for Ar or Ar₁ include methyl, methoxy,fluoromethyl, difluoromethyl, perfluoromethyl (trifluoromethyl),1-fluoroethyl, 2-fluoroethyl, ethoxy, fluoro, chloro, and bromo, andparticularly methyl, bromo, chloro, perfluoromethyl, perfluoromethoxy,methoxy, and fluoro. Preferred substitution patterns for Ar or Ar₁ are4-substituted or 3,4-disubstituted phenyl.

Compounds of the invention are further described in the next section.

B. COMPOUNDS

The invention features compounds of formula (I) as described in theSummary section.

Preferred compounds include those wherein:

-   -   (a) Ar₂ is selected from formulae (e);    -   (b) Ar₂ is selected from formulae (f);    -   (c) Ar₂ is selected from formula (a)-(d);    -   (d) R¹ is halogen, C₁₋₅ alkoxy, hydroxy, C₁₋₅ alkyl, cyano,        nitro, R^(a)R^(b)N or is taken together with R²⁷;    -   (e) R¹ is taken together with R²⁷;    -   (f) R¹ and R²⁷ taken together are selected from:        -   (1) —CH₂NR⁹—(C═O)—        -   (2) OCH₂(C═O)—        -   (3) —CH₂CH₂(C═O)—        -   (4) —CH₂—O(C═O)—        -   (5) —CH₂S(C═O)—        -   (6) —O(C═O)—        -   (7) —CH₂(C═O)—        -   (8) —NR⁹(C═O)—        -   (9) —NR⁹(SO₂)—        -   (10) —CH₂NR⁹SO₂—        -   (11) —NR⁹CH₂(C═O)— and —SCH2(C═O)—    -   (g) R¹ and R²⁷ taken together are selected from:        -   a) —CH₂—(C═O)—        -   b) —O(C═O)—        -   c) —CH₂CH₂—        -   d) —S(C═O)—        -   e) —N═N—        -   f) —NR⁹SO₂—        -   g) —N═CR⁹—        -   h) —NR⁹(C═O)— and        -   i) —CH═CH—;    -   (h) R² is hydrogen, halogen, C₁₋₅ alkoxy, C₁₋₅ alkyl, cyano, or        R^(e)R^(f)N, where R^(e) and R^(f) are H or C₁₋₅ alkyl, or are        taken together to form a 5-7 membered heterocyclic ring;    -   (i) R³ is hydrogen, halogen, C₁₋₅ alkoxy, C₁₋₅ alkyl, cyano,        nitro, or R^(g)R^(h)N, where R^(e) and R^(f) are H or C₁₋₅        alkyl, or are taken together to form a 5-7 membered heterocyclic        ring;    -   (j) R⁵ and R⁶ are independently selected from hydrogen and C₁₋₃        alkyl;    -   (k) one of R⁵ and R⁶ is H;    -   (l) R⁵ and R⁶ are each H;    -   (m) one of R⁷ and R⁸ is H and the other is 5-7 membered        carbocyclyl or heterocyclyl;    -   (n) R⁷ and R⁸ are taken together to form an optionally        substituted 5- to 7-membered carbocyclic or heterocyclic ring;    -   (o) R⁷ and R⁸ taken together form a six-membered heterocyclyl;    -   (p) R⁷ and R⁸ taken together form pyridinyl, pyrimidinyl, or        piperazinyl, optionally N-substituted with —(C═O)R⁴, SO₂—R⁴, or        —(C═O)NHR⁴;    -   (q) each of R^(a), R^(e), R^(m), and R^(o) is independently        selected from hydrogen, C₁₋₅ alkyl, C₂₋₈ acyl, and the        respective ROC═O, RRNC═O, RSO, RSO₂, and RRNSO₂ groups;    -   (r) each of R^(a), R^(e), R^(m), R^(o), R^(b), R^(f), R^(n), and        R^(p) is independently selected from hydrogen and C₁₋₅ alkyl;        or, independently, R^(a) and R^(b), R^(e) and R^(f), R^(m) and        R^(n), and R^(o) and R^(p), taken together, form an optionally        substituted 4- to 7-membered carbocyclic or heterocyclic ring;    -   (s) (1)R^(a) and R^(b) taken together are independently        morpholinyl, piperidinyl, or pyrrolidinyl; (2) R^(e) and R^(f)        taken together are morpholinyl, piperidinyl, or pyrrolidinyl;        or (3) both (1) and (2) apply;    -   (t) each of R^(c) and R^(d), R^(i) and R^(j), R^(k) and R^(l) is        independently hydrogen or C₁₋₅ alkyl, alternatively, R^(c) and        R^(d), R^(i) and Rj, and R^(k) and R^(l), independently, can be        taken together to form an optionally substituted 4- to        7-membered heterocyclic ring, which ring may be saturated,        unsaturated or aromatic;    -   (u) R^(c) and R^(d), R^(i) and R^(j), and R^(k) and R^(l),        independently, are taken together to form an optionally        substituted 4- to 7-membered heterocyclic ring, which ring may        be saturated, unsaturated or aromatic;    -   (v) each of R^(b), R^(f), R^(n), R^(p), R³², R³³, R³⁴, R³⁵, R³⁶,        R³⁷, R³⁹, and R⁴⁰ is independently H or C₁₋₅ alkyl;    -   (w) each of R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁹, R³⁸, and R⁴¹ is        independently H or C₁₋₅ alkyl;    -   (x) R^(g) is C₁₋₅ alkyl, C₂₋₈ acyl, R¹⁷OC═O, R¹⁷R¹⁸NC═O, R¹⁶S,        R¹⁶SO, R¹⁶SO₂, or R¹⁷R¹⁸NSO₂; and R^(h) hydrogen or C₁₋₅ alkyl;        alternatively, R^(g) and R^(h) can be taken together to form an        optionally substituted 4- to 7-membered heterocyclic ring;    -   (y) R¹⁷ and R¹⁸ independently are hydrogen or C₁₋₅ alkyl;    -   (z) n is 1;    -   (aa) n is 0;    -   (bb) G is C₃₋₄ alkanediyl, optionally substituted with hydroxy,        halogen, (L)-C₁₋₅ alkyloxy, or [(L)-C₁₋₅ alkylene]amino;    -   (cc) G is C₃ alkanediyl, optionally substituted with hydroxy,        (L)-C₁₋₅ alkyloxy, or [(L)-C₁₋₅ alkylene]amino;    -   (dd) each of R²⁰ and R²¹ is independently selected from        hydrogen, halogen, C₁₋₅ alkoxy, C₁₋₅ alkyl, cyano, nitro, and        R^(m)R^(n)N or R^(o)R^(p)N, respectively;    -   (ee) each of R²⁰ and R²¹ is independently selected from        hydrogen, halogen, C₁₋₃ alkyl, and R^(m)R^(n)N or R^(o)R^(p)N,        respectively;    -   (ff) Ar represents a monocyclic ring, optionally substituted        with 1 to 2 substituents-selected from halogen, C₁₋₅ alkyl,        cyano, nitro, R²²R²³N, halomethyl, and halomethoxy;    -   (gg) Ar is a six membered ring substituted with between 1 and 2        substituents independently selected from methyl, halogen, CF₃,        and OCF₃, said substituent or substituents being at the 4-        position, or at the 3- and 4-positions, respectively;    -   (hh) each of R²², R²³, and R²⁴ is hydrogen or C₁₋₅ alkyl;    -   (ii) R²⁵ and R²⁶ independently are hydrogen or C₁₋₅ alkyl; or,        alternatively, R²⁵ and R²⁶ can be taken together to form an        optionally substituted 4- to 7-membered heterocyclic ring;    -   (jj) each of R²⁵ and R²⁶ is independently hydrogen or C₁₋₅        alkyl;    -   (kk) W is NR²⁷;    -   (ll) W is CHR²⁸, and R²⁸ is hydrogen or C₁₋₅ alkyl;    -   (mm) R²⁹ is C₁₋₅ alkyl; or R³⁰ and R³¹ are independently        selected from hydrogen and C₁₋₅ alkyl, or R³⁰ and R³¹ are taken        together to form a 5-6 membered heterocyclyl;    -   (nn) Ar₂ is formula (e) and R¹ is halogen, C₁₋₅ alkoxy, hydroxy,        C₁₋₅ alkyl, cyano, nitro, and R^(a)R^(b)N, or R¹ can be taken        together with R²⁷ as provided below; R² is hydrogen, halogen,        C₁₋₅ alkoxy, C₁₋₅ alkyl, or R^(e)R^(f)N; R³ is hydrogen,        halogen, C₁₋₅ alkoxy, hydroxy, C₁₋₅ alkyl, cyano, R^(g)R^(h)N;        R⁵ and R⁶ are independently selected from hydrogen and C₁₋₃        alkyl;    -   (oo) R⁷ and R⁸ independently are taken together to form an        optionally substituted 5- to 7-membered carbocyclic or        heterocyclic ring, which ring may be saturated, unsaturated or        aromatic;    -   (pp) each of R^(a), R^(e), R^(m) , and R^(o) is independently        selected from hydrogen, C₁₋₅ alkyl, C₂₋₈ acyl, and the        respective ROC═O, RRNC═O, RS, RSO, RSO₂, and RRNSO₂ groups;    -   (qq) each of R^(b), R^(f), R^(n), and R^(p), is independently        selected from hydrogen and C₁₋₅ alkyl; each of R¹¹, R¹², R¹³,        R¹⁴, R¹⁵, R¹⁶, R¹⁹, and R³⁸ is independently C₁₋₅ alkyl; each of        R^(c) and R^(d), R^(i) and R^(j), R^(k) and R^(l), R³² and R³³,        R³⁴ and R³⁵, R³⁶ and R³⁷ are independently are hydrogen or C₁₋₅        alkyl, or are taken together to form an optionally substituted        4- to 7-membered heterocyclic ring;    -   (rr) R^(g) is hydrogen, C₁₋₅ alkyl, C₂₋₈ acyl, R¹⁷OC═O,        R¹⁷R¹⁸NC═O, R¹⁶S, R¹⁶SO, R¹⁶SO₂, or R¹⁷R¹⁸NSO₂; R^(h) is        hydrogen or C₁₋₅ alkyl; alternatively, R^(g) and R^(h) can be        taken together to form an optionally substituted 4- to        7-membered heterocyclic ring; R¹⁷ and R¹⁸ independently are        hydrogen or C₁₋₅ alkyl; n is 0 or 1;    -   (ss) G is C₃₋₄ alkenediyl or C₃₋₄ alkanediyl, optionally        substituted with hydroxy, halogen, C₁₋₅ alkyloxy, (L)-C₁₋₅        alkoxy, or [(L)-C₁₋₅ alkylene]amino; L is amino, mono- or        di-C₁₋₅ alkylamino, pyrrolidinyl, morpholinyl, piperidinyl        homopiperidinyl, or piperazinyl, wherein available ring        nitrogens may be optionally substituted with C₁₋₅ alkyl, benzyl,        C₁₋₅ alkylcarbonyl, or C₁₋₅ alkyloxycarbonyl;    -   (tt) Y_(e) is nitrogen or R²⁰C; Z_(e) is nitrogen or R²¹C    -   (uu) R²⁰ and R²¹ are independently selected from hydrogen,        halogen, C₁₋₅ alkoxy, C₁₋₅ alkyl, cyano, nitro, and R^(m)R^(n)N        or R^(o)R^(p)N, respectively; alternatively, R³ and R²⁰ or R³        and R²¹ can be taken together to form an optionally substituted        5- or 6-membered carbocyclic or heterocyclic ring;    -   (vv) Ar represents a monocyclic or bicyclic aryl or heteroaryl        ring, optionally substituted with between 1 and 3 substituents        independently selected from halogen, C₁₋₅ alkoxy, C₁₋₅ alkyl,        cyano, nitro, R²²R²³N, R²⁴SO₂, R²⁴OC═O, R²⁵R²⁶NC═O, CF₃, OCF₃,        CF₃S, and C₁₋₅ alkylthio; R²² is hydrogen, C₁₋₅ alkyl, phenyl,        benzyl, phenethyl, C₁₋₅ heterocyclyl, C₂₋₈ acyl, aroyl, R²⁴OC═O,        R²⁵R²⁶NC═O, R²⁴SO, R²⁴SO₂, or R²⁵R²⁶NSO₂; R²³ is hydrogen or        C₁₋₅ alkyl;    -   (ww) alternatively, R²² and R²³ can be taken together to form an        optionally substituted 4- to 7-membered heterocyclic ring; R²⁴        is hydrogen or C₁₋₅ alkyl; R²⁵ and R²⁶ are independently        hydrogen or C₁₋₅ alkyl; or, alternatively, R²⁵ and R²⁶ can be        taken together to form an optionally substituted 4- to        7-membered heterocyclic; W is NR²⁷or CHR²⁸; R²⁷ is hydrogen,        C₁₋₅ alkyl, R²⁹OC═O, R³⁰R³¹NC═O, R²⁹SO, R²⁹SO₂, or R³⁰R³¹NSO₂;        or, alternatively, R²⁷ and R¹ can be taken together to form an        optionally substituted 5- or 6-membered heterocyclic ring, which        ring may be saturated, unsaturated or aromatic; R²⁸ is hydrogen,        hydroxy, C₁₋₅ heterocyclyl, phenyl, or C₁₋₅ alkyl; R²⁹ is C₁₋₅        alkyl; R³⁰ and R³¹ are independently selected from hydrogen,        C₁₋₅ alkyl; alternatively, R³⁰ and R³¹ can be taken together to        form an optionally substituted 4- to 7-membered heterocyclic;    -   (xx) one of R⁵ and R⁶ is H; R⁷ and R⁸ are taken together to form        an optionally substituted 6-membered carbocyclic or heterocyclic        ring; and Ar represents a monocyclic ring, optionally        substituted with 1 to 2 substituents selected from halogen, C₁₋₅        alkyl, cyano, nitro, R²²R²³N, CF₃ and OCF₃;    -   (yy) both R⁵ and R⁶ are each H, and Ar is a six membered ring        substituted with between 1 and 2 substituents independently        selected from halogen, methyl, CF₃, and OCF₃, said substituent        or substituents being at the 4-position, or at the 3- and        4-positions;    -   (zz) a R⁷ and R⁸ taken together form tetrahydropyridinyl,        optionally N-substituted with —(C═O)R⁴, SO₂—R⁴, or —(C═O)NHR⁴;    -   (aaa) X_(f) is C═O, SO₂, or CHR^(1f), and Y_(f) is O or NR^(2f),        where R^(2f) is H, C₁₋₅ alkyl, C₂₋₅ heterocyclyl, C₁₋₅        cyanoalkyl, or (C₁₋₅ alkoxycarbonyl)C₁₋₅ alkylene;    -   (bbb) R^(2f) is H, C₁₋₃ alkyl, or a C₂₋₅ heterocyclyl;    -   (ccc) X_(f) is C═O, and Y_(f) is O, CHR^(2f) or NR^(2f), where        R^(2f) is H, C₁₋₅ alkyl, C₂₋₅ heterocyclyl, C₁₋₅ cyanoalkyl, or        (C₁₋₅ alkoxycarbonyl)C₁₋₅ alkylene;    -   (ddd) X_(f) is C═O and Y_(f) is O;    -   (eee) m is 0 and p is 0; m is 0 and p is 1; or m is 1 and p is        0;    -   (fff) p is 0;    -   (ggg) R^(z) is H;    -   (hhh) R^(z) is OH;    -   (iii) R^(z) is absent;    -   (jjj) R²⁰ and R³ taken together are a six-membered carbocyclic        or heterocyclic ring optionally substituted with between 1 and 3        substituents independently selected from halo, C₁₋₃ alkoxy,        di(C₁₋₃ alkyl)amino, and C₂₋₅ acyl;    -   (kkk) each of R²⁰ and R³ is H; and    -   (lll) combinations of the above.

Specific preferred compounds include:

1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one;1-(1-{3-[3-(3,4-Dichloro-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one; 3-(3,4-Dichloro-phenyl)-1-{3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid amide;6-Chloro-1-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one;3-(3,4-Dichloro-phenyl)-1-{3-[4-(3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid amide;[3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-acetonitrile;(3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-aceticacid ethyl ester;5-Chloro-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-dihydro-benzoimidazol-2-one;1-{3-[4-(6-Chloro-3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3-(3,4-dichloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid amide;3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,5-dimethyl-1,3-dihydro-benzoimidazol-2-one;3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one;3-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-methoxy-1,3-dihydro-imidazo[4,5-b]pyridin-2-one;3-(4-Bromo-phenyl)-1-{2-hydroxy-3-[4-(5-methoxy-2-oxo-1,2-dihydro-imidazo[4,5-b]pyridin-3-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid amide;3-(1-{2-Hydroxy-3-[5-methanesuifonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-methoxy-1-methyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one;5-Dimethylamino-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one;6-Chloro-1-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-one;1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-one;4-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-benzo[1,4]oxazin-3-one;4-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-benzo[1,4]oxazin-3-one;and1-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinazolin-2-one.

Furthermore, preferred compounds include those wherein Ar or Ar₁ isselected from 4-trifluoromethylphenyl, 4-bromophenyl, 4-chlorophenyl,4-chloro-3-methylphenyl and 3,4-dichlorophenyl.

Related Compounds

The invention provides the disclosed compounds and closely related,pharmaceutically acceptable forms of the disclosed compounds, such assalts, esters, amides, acids, hydrates or solvated forms thereof; maskedor protected forms; and racemic mixtures, or enantiomerically oroptically pure forms. Related compounds also include compounds of theinvention that have been modified to be detectable, e.g., isotopicallylabelled with ¹⁸F for use as a probe in positron emission tomography(PET) or single-photon emission computed tomography (SPECT).

The invention also includes disclosed compounds having one or morefunctional groups (e.g., hydroxyl, amino, or carboxyl) masked by aprotecting group. See, e.g., Greene and Wuts, Protective Groups inOrganic Synthesis, 3^(rd) ed., (1999) John Wiley & Sons, NY. Some ofthese masked or protected compounds are pharmaceutically acceptable;others will be useful as intermediates. Synthetic intermediates andprocesses disclosed herein, and minor modifications thereof, are alsowithin the scope of the invention.

Hydroxyl Protecting Groups

Protection for the hydroxyl group includes methyl ethers, substitutedmethyl ethers, substituted ethyl ethers, substitute benzyl ethers, andsilyl ethers.

Substituted Methyl Ethers

Examples of substituted methyl ethers include methyoxymethyl, methylthiomethyl, t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl,benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl,guaiacolmethyl, t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl,2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl,tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl,1-methoxycyclohexyl, 4-methoxytetrahydropyranyl,4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxido, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl,1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl and2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl.

Substituted Ethyl Ethers

Examples of substituted ethyl ethers include 1-ethoxyethyl,1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, andbenzyl.

Substituted Benzyl Ethers

Examples of substituted benzyl ethers include p-methoxybenzyl,3,4-dimethoxybenzyl, onitrobenzyl, p-nitrobenzyl, p-halobenzyl,2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4-picolyl,3-methyl-2-picolyl N-oxido, diphenylmethyl, p, p′-dinitrobenzhydryl,5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl,p-methoxyphenyidiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(tmethoxyphenyl)methyl, 4-(4′-bromophenacyloxy)phenyidiphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(/midazol-1-ylmethyl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodithiolan-2-yl, and benzisothiazolyl S,S-dioxido.

Silyl Ethers

Examples of silyl ethers include trimethylsilyl, triethylsilyl,triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl,dimethylthexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl,tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl,and t-butylmethoxyphenylsilyl.

Esters

In addition to ethers, a hydroxyl group may be protected as an ester.Examples of esters include formate, benzoylformate, acetate,chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate,methoxyacetate, triphenylmethoxyacetate, phenoxyacetate,p-chlorophenoxyacetate, p-P-phenylacetate, 3-phenylpropionate,4-oxopentanoate(levulinate), 4,4-(ethylenedithio)pentanoate, pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, Rphenylbenzoate,2,4,6-trimethylbenzoate(mesitoate)

Carbonates

Examples of carbonate protecting groups include methyl,9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl,2-(phenylsulfonyl)ethyl, 2-(triphenylphosphonio)ethyl, isobutyl, vinyl,allyl, p-nitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl,onitrobenzyl, p-nitrobenzyl, S-benzyl thiocarbonate,4-ethoxy-1-naphthyl, and methyl dithiocarbonate.

Assisted Cleavage

Examples of assisted cleavage include 2-iodobenzoate, 4-azidobutyrate,4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate,4-(methylthiomethoxy)butyrate, and 2-(methylthiomethoxymethyl)benzoate.

Miscellaneous Esters

Examples of miscellaneous esters include2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate(tigloate),o-(methoxycarbonyl)benzoate, p-P-benzoate, α-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, N-phenylcarbamate, borate,dimethylphosphinothioyl, and 2,4-dinitrophenylsulfenate.

Sulfonates

Examples of sulfonates include sulfate, methanesulfonate(mesylate),benzylsulfonate, and tosylate.

Amino Protecting Groups

Protection for the amino group includes carbamates, amides, and special—NH protective groups.

Examples of carbamates include methyl and ethyl carbamates, substitutedethyl carbamates, assisted cleavage carbamates, photolytic cleavagecarbamates, urea-type derivatives, and miscellaneous carbamates.

Carbamates

Examples of methyl and ethyl carbamates include methyl and ethyl,9-fluorenylmethyl, 9-(2-sulfo)fluorenylmethyl,9-(2,7-dibromo)fluorenylmethyl,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl,and 4-methoxyphenacyl.

Substituted Ethyl

Examples of substituted ethyl carbamates include 2,2,2-trichloroethyl,2-trimethylsilylethyl, 2-phenylethyl, 1-(1-adamantyl)-1-methylethyl,1,1-dimethyl-2-haloethyl, 1,1-dimethyl-2,2-dibromoethyl;1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1-(4-biphenylyl)ethyl,1-(3,5-di-t-butylphenyl)-1-methylethyl, 2-(2′- and 4′-pyridyl)ethyl,2-(N,N-dicyclohexylcarboxamido)ethyl, t-butyl, 1-adamantyl, vinyl,allyl, 1-isopropylallyl, cinnamyl, 4-nitrocinnamyl, 8-quinolyl,N-hydroxypiperidinyl, alkyldithio, benzyl, pmethoxybenzyl, pnitrobenzyl,p-bromobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl,4-methylsulfinylbenzyl, 9-anthrylmethyl and diphenylmethyl.

Assisted Cleavage

Examples of assisted cleavage include 2-methylthioethyl,2-methylsulfonylethyl, 2-(ptoluenesulfonyl)ethyl,[2-(1,3-dithianyl)]methyl, 4-methylthiophenyl, 2,4-dimethylthiophenyl,2-phosphonioethyl, 2-triphenylphosphonioisopropyl,1,1-dimethyl-2-cyanoethyl, m-chloro-p-acyloxybenzyl,p-(dihydroxyboryl)benzyl, 5-benzisoxazolylmethyl, and2-(trifluoromethyl)-6-chromonylmethyl.

Photolytic Cleavage

Examples of photolytic cleavage include rmnitrophenyl,3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, andphenyl(o-nitrophenyl)methyl.

Urea-Type Derivatives

Examples of urea-type derivatives include phenothiazinyl-(10)-carbonylderivative, N′-ptoluenesulfonylaminocarbonyl, andN′-phenylaminothiocarbonyl.

Miscellaneous Carbamates

Examples of miscellaneous carbamates include t-amyl, S-benzylthiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl,cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl,2,2-dimethoxycarbonylvinyl, o-(N,N-dimethylcarboxamido)benzyl,1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl, 1,1-dimethylpropynyl,di(2-pyridyl)methyl, 2-furanylmethyl, 2-iodoethyl, isobornyl, isobutyl,isonicotinyl, p-(p′-methoxyphenylazo)benzyl, 1-methylcyclobutyl,1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl,1-methyl-1-(3,5-dimethoxyphenyl)ethyl,1-methyl-1-(p-phenylazophenyl)ethyl, 1-methyl-1-phenylethyl,1-methyl-1-(4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl,2,4,6-tri-t-butylphenyl, 4-(trimethylammonium)benzyl, and2,4,6-trimethylbenzyl.

Examples of Amides Include:

Amides

N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl,N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-picolinoyl,N-3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, N-benzoyl,N-pphenylbenzoyl.

Assisted Cleavage

N-o-nitrophenylacetyl, N-o-nitrophenoxyacetyl, N-acetoacetyl,(N′-dithiobenzyloxycarbonylamino)acetyl, N-3-(p-hydroxyphenyl)propionyl,N-3-(o-nitrophenyl)propionyl, N-2-methyl-2-(onitrophenoxy)propionyl,N-2-methyl-2-(o-phenylazophenoxy)propionyl, N-4-chlorobutyryl,N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl, N-acetylmethioninederivative, N-onitrobenzoyl, N-o-(benzoyloxymethyl)benzoyl, and4,5-diphenyl-3-oxazolin-2-one.

Cyclic Imide Derivatives

N-phthalimide, N-dithiasuccinoyl, N-2,3-diphenylmaleoyl,N-2,5-dimethylpyrrolyl, N-1,1,4,4-tetramethyldisilylazacyclopentaneadduct, 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one,5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, and1-substituted 3,5-dinitro-4-pyridonyl.

Special—NH Protective Groups

Examples of special NH protective groups include

N-Alkyl and N-Aryl Amines

N-methyl, N-allyl, N-[2-(trimethylsilyl)ethoxy]methyl,N-3-acetoxypropyl, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl),quaternary ammonium salts, N-benzyl, N-di(4-methoxyphenyl)methyl,N-5-dibenzosuberyl, N-triphenylmethyl,N-(4-methoxyphenyl)diphenylmethyl, N-9-phenylfluorenyl,N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl, andN-2-picolylamine N′-oxide.

Imine Derivatives

N-1,1-dimethylthiomethylene, N-benzylidene, N-pmethoxybenzylidene,N-diphenylmethylene, N-[(2-pyridyl)mesityl]methylene, andN-(N′,N′-dimethylaminomethylene).

Protection for the Carbonyl Group

Acyclic Acetals and Ketals

Examples of acyclic acetals and ketals include dimethyl,bis(2,2,2-trichloroethyl), dibenzyl, bis(2-nitrobenzyl) and diacetyl.

Cyclic Acetals and Ketals

Examples of cyclic acetals and ketals include 1,3-dioxanes,5-methylene-1,3-dioxane, 5,5-dibromo-1,3-dioxane,5-(2-pyridyl)-1,3-dioxane, 1,3-dioxolanes, 4-bromomethyl-1,3-dioxolane,4-(3-butenyl)-1,3-dioxolane, 4-phenyl-1,3-dioxolane,4-(2-nitrophenyl)-1,3-dioxolane, 4,5-dimethoxymethyl-1,3-dioxolane,O,O′-phenylenedioxy and 1,5-dihydro-3H-2,4-benzodioxepin.

Acyclic Dithio Acetals and Ketals

Examples of acyclic dithio acetals and ketals include S,S′-dimethyl,S,S′-diethyl, S,S′-dipropyl, S,S′-dibutyl, S,S′-dipentyl, S,S′-diphenyl,S,S′-dibenzyl and S,S′-diacetyl.

Cyclic Dithio Acetals and Ketals

Examples of cyclic dithio acetals and ketals include 1,3-dithiane,1,3-dithiolane and 1,5-dihydro-3H-2,4-benzodithiepin.

Acyclic Monothio Acetals and Ketals

Examples of acyclic monothio acetals and ketals includeO-trimethylsilyl-S-alkyl, O-methyl-S-alkyl or —S-phenyl andO-methyl-S-2-(methylthio)ethyl.

Cyclic Monothio Acetals and Ketals

Examples of cyclic monothio acetals and ketals include 1,3-oxathiolanes.

Miscellaneous Derivatives

O-Substituted Cyanohydrins

Examples of O-substituted cyanohydrins include O-acetyl,O-trimethylsilyl, O-1-ethoxyethyl and O-tetrahydropyranyl.

Substituted Hydrazones

Examples of substituted hydrazones include N,N-dimethyl and2,4-dinitrophenyl.

Oxime Derivatives

Examples of oxime derivatives include O-methyl, O-benzyl andO-phenylthiomethyl.

Imines

Substituted Methylene Derivatives, Cyclic Derivatives

Examples of substituted methylene and cyclic derivatives includeoxazolidines, 1-methyl-2-(1′-hydroxyalkyl)imidazoles,N,N′-dimethylimidazolidines, 2,3-dihydro-1,3-benzothiazoles,diethylamine adducts, and methylaluminumbis(2,6-di-t-butyl-4-methylphenoxide)(MAD)complex.

Protection for the Carboxyl Group

Esters

Substituted Methyl Esters

Examples of substituted methyl esters include 9-fluorenylmethyl,methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl,methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl,phenacyl, pbromophenacyl, α-methylphenacyl, p-methoxyphenacyl,carboxamidomethyl, and N-phthalimidomethyl.

2-Substituted Ethyl Esters

Examples of 2-substituted ethyl esters include 2,2,2-trichloroethyl,2-haloethyl, ω-chloroalkyl, 2-(trimethylsilyl)ethyl, 2-methylthioethyl,1,3-dithianyl-2-methyl, 2-(p-nitrophenylsulfenyl)ethyl,2-(p-toluenesulfonyl)ethyl, 2-(2′-pyridyl)ethyl,2-(diphenylphosphino)ethyl, 1-methyl-1-phenylethyl, t-butyl,cyclopentyl, cyclohexyl, allyl, 3-buten-1-yl,4-(trimethylsilyl)-2-buten-1-yl, cinnamyl, α-methylcinnamyl, phenyl,p-(methylmercapto)phenyl and benzyl.

Substituted Benzyl Esters

Examples of substituted benzyl esters include triphenylmethyl,diphenylmethyl, bis(o-nitrophenyl)methyl, 9-anthrylmethyl,2-(9,10-dioxo)anthrylmethyl, 5-dibenzosuberyl, 1-pyrenylmethyl,2-(trifluoromethyl)-6-chromylmethyl, 2,4,6-trimethylbenzyl,p-bromobenzyl, onitrobenzyl, p-nitrobenzyl, p-methoxybenzyl,2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl, 4-sulfobenzyl, piperonyl,4-picolyl and p-P-benzyl.

Silyl Esters

Examples of silyl esters include trimethylsilyl, triethylsilyl,t-butyldimethylsilyl, i-propyldimethylsilyl, phenyldimethylsilyl anddi-t-butylmethylsilyl.

Activated Esters

Examples of activated esters include thiols.

Miscellaneous Derivatives

Examples of miscellaneous derivatives include oxazoles,2-alkyl-1,3-oxazolines, 4-alkyl-5-oxo-1,3-oxazolidines,5-alkyl-4-oxo-1,3-dioxolanes, ortho esters, phenyl group andpentaaminocobalt(III) complex.

Stannyl Esters

Examples of stannyl esters include triethylstannyl andtri-n-butylstannyl.

Amides and Hydrazides

Amides

Examples of amides include N,N-dimethyl, pyrrolidinyl, piperidinyl,5,6-dihydrophenanthridinyl, onitroanilides, N-7-nitroindolyl,N-8-Nitro-1,2,3,4-tetrahydroquinolyl, and p-P-benzenesulfonamides.

Hydrazides

Examples of hydrazides include N-phenyl and N,N′-diisopropyl hydrazides.

C. SYNTHESIS

The compounds of the present invention may be prepared by conventionalsynthetic organic chemistry and by matrix or combinatorial methodsaccording to Schemes 1 to 8 below, and Examples 1 to 31. Those ofordinary skill in the art will be able to modify and adapt the guidanceprovided herein to make the disclosed compounds.

D. FORMULATION AND ADMINISTRATION

The present compounds inhibit the proteolytic activity of humancathepsin S and therefore are useful as a medicine especially in methodsfor treating patients suffering from disorders or conditions which aremodulated or regulated by the inhibition of cathepsin S activity.

The invention features a method for treating a subject with a conditionmediated by cathepsin S, said method comprising administering to thesubject a therapeutically effective amount of a pharmaceuticalcomposition comprising a compound of the invention. The invention alsoprovides a method for inhibiting cathepsin S activity in a subject,wherein the method comprises administering to the subject atherapeutically effective amount of a pharmaceutical compositioncomprising a compound of the invention. A third method is a method fortreating an autoimmune disease, or inhibiting the progression of anautoimmune disease, in a subject, said method comprising administeringto the subject a therapeutically effective amount of a pharmaceuticalcomposition comprising a disclosed compound. The autoimmune disease canbe, for example, lupus, rheumatoid arthritis, or preferably, asthma. Theinvention also provides a method for treating or inhibiting theprogression of tissue transplant rejection in a subject, the methodcomprising administering to the subject a therapeutically effectiveamount of a pharmaceutical composition comprising a compound of theinvention. The administration step can occur before, during, and/orafter a tissue transplant procedure.

In view of their inhibitory effect on the proteolytic activity of humancathepsin S the compounds of the present invention may be formulatedinto various pharmaceutical forms for administration purposes. Toprepare these pharmaceutical compositions, an effective amount of aparticular compound, in base or acid addition salt form, as the activeingredient is intimately mixed with a pharmaceutically acceptablecarrier.

A carrier may take a wide variety of forms depending on the form ofpreparation desired for administration. These pharmaceuticalcompositions are desirably in unitary dosage form suitable, preferably,for oral administration or parenteral injection. For example, inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed. These include water, glycols,oils, alcohols and the like in the case of oral liquid preparations suchas suspensions, syrups, elixirs and solutions; or solid carriers such asstarches, sugars, kaolin, lubricants, binders, disintegrating agents andthe like in the case of powders, pills, capsules and tablets. In view oftheir ease in administration, tablets and capsules represent the mostadvantageous oral dosage unit form, in which case solid pharmaceuticalcarriers are generally employed. For parenteral compositions, thecarrier will usually comprise sterile water, at least in large part,though other ingredients, for example, to aid solubility, may beincluded. Injectable solutions, for example, may be prepared in whichthe carrier comprises saline solution, glucose solution or a mixture ofsaline and glucose solution. Injectable suspensions may also be preparedin which case appropriate liquid carriers, suspending agents and thelike may be employed. In the compositions suitable for percutaneousadministration, the carrier optionally comprises a penetration enhancingagent and/or a suitable wetting agent, optionally combined with suitableadditives of any nature in minor proportions, which additives do notcause a significant deleterious effect to the skin. Such additives mayfacilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as aspot-on, as an ointment. Acid addition salts of the compounds of formulaI, due to their increased water solubility over the corresponding baseform, are more suitable in the preparation of aqueous compositions.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification herein refers to physically discrete units suitable asunitary dosages, each unit containing a predetermined quantity of activeingredient calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. Examples of suchdosage unit forms are tablets (including scored or coated tablets),capsules, pills, powder packets, wafers, injectable solutions orsuspensions, teaspoonfuls, tablespoonfuls and the like, and segregatedmultiples thereof.

Pharmaceutically acceptable acid addition salts include thetherapeutically active non-toxic acid addition salt forms which thedisclosed compounds are able to form. The latter can conveniently beobtained by treating the base form with an appropriate acid. Appropriateacids comprise, for example, inorganic acids such as hydrohalic acids,e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric andthe like acids; or organic acids such as, for example, acetic,propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic,maleic, fumaric, malic, tartaric, citric, methanesulfonic,ethanesulfonic, benzenesulfonic, ptoluenesulfonic, cyclamic, salicylic,paminosalicylic, palmoic and the like acids. The term addition salt alsocomprises the solvates which the disclosed componds, as well as thesalts thereof, are able to form. Such solvates are for example hydrates,alcoholates and the like. Conversely the salt form can be converted bytreatment with alkali into the free base form.

Stereoisomeric form defines all the possible isomeric forms which thecompounds of formula (I) may possess. Unless otherwise mentioned orindicated, the chemical designation of compounds denotes the mixture ofall possible stereochemically isomeric forms, said mixtures containingall diastereomers and enantiomers of the basic molecular structure. Morein particular, stereogenic centers may have the (R)- or(S)-configuration; substituents on bivalent cyclic saturated radicalsmay have either the cis- or trans-configuration. The inventionencompasses stereochemically isomeric forms including diastereoisomers,as well as mixtures thereof in any proportion of the disclosedcompounds. The disclosed compounds may also exist in their tautomericforms. Such forms although not explicitly indicated in the above andfollowing formulae are intended to be included within the scope of thepresent invention.

Those of skill in the treatment of disorders or conditions mediated bythe cathepsin S enzyme could easily determine the effective daily amountfrom the test results presented hereinafter and other information. Ingeneral it is contemplated that a therapeutically effective dose wouldbe from 0.001 mg/kg to 5 mg/kg body weight, more preferably from 0.01mg/kg to 0.5 mg/kg body weight. It may be appropriate to administer thetherapeutically effective dose as two, three, four or more sub-doses atappropriate intervals throughout the day. Said sub-doses may beformulated as unit dosage forms, for example, containing 0.05 mg to 250mg, and in particular 0.5 to 50 mg of active ingredient per unit dosageform. Examples include 2 mg, 4 mg, 7 mg, 10 mg, 15 mg, 25 mg, and 35 mgdosage forms. Compounds of the invention may also be prepared intime-release or subcutaneous or transdermal patch formulations.Disclosed compound may also be formulated as a spray or other topical orinhalable formulations.

The exact dosage and frequency of administration depends on theparticular compound of formula (I) used, the particular condition beingtreated, the severity of the condition being treated, the age, weightand general physical condition of the particular patient as well asother medication the patient may be taking, as is well known to thoseskilled in the art. Furthermore, it is evident that said effective dailyamount may be lowered or increased depending on the response of thetreated patient and/or depending on the evaluation of the physicianprescribing the compounds of the instant invention. The effective dailyamount ranges mentioned herein are therefore only guidelines.

The next section includes detailed information relating to thepreparation, characterization, and use of the disclosed compounds.

E. EXAMPLES Example 1

2-(1-{3-[5-Acetyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-ylamino)-benzonitrile.A.1-[3-(4-Chloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

To a stirred solution of 50 g (0.35 mol) of N-acetyl-4-piperidone and 31g (0.35 mol) of morpholine in benzene (350 mL) was added a catalyticamount (˜0.25 g) of p-toluenesulfonic acid. The mixture was heated toreflux for 10 h with a Dean-Stark trap. The solvent was removed underreduced pressure to give a brown oil. The crude product was diluted withCH₂Cl₂ (175 mL) and 50.0 mL (0.35 mol) of Et₃N was added. The mixturewas cooled to 0° C. and a solution of 45.0 mL (0.35 mol) of4-chlorobenzoyl chloride in CH₂Cl₂ (50 mL) was added slowly by droppingfunnel over 1 h. The mixture was allowed to warm to room temperature andstirred overnight. The reaction was then diluted with 1 N HCl (150 mL)and stirred vigorously for 3 h. The aqueous layer was extracted withCH₂Cl₂ (3×250 mL) and the combined extracts were dried over Na₂SO₄ andthe solvent was removed under reduced pressure. The crude oil wasdiluted with EtOH (350 mL) and cooled to 0° C. To this stirred solutionwas slowly added 33.0 mL (1.06 mol) of hydrazine and the mixture wasallowed to warm to room temperature and stir overnight during which timea white precipitate formed. The volume of the reaction was reduced to˜150 mL and EtOAc (750 mL) was added to the mixture. The suspension wasstirred vigorously for 2 h and was filtered then washed with EtOAc(2×200 mL) and dried under vacuum to afford 41.4 g (42% over 3 steps) ofa pale yellow solid. TLC (silica, 5% MeOH/CH₂Cl₂): R_(f)=0.3. MS(electrospray): m/z calculated for C₁₄H₁₄ClN₃O [M+H]⁺276.08, observed276.0. ¹H NMR (400 MHz, CDCl₃, a mixture of amide rotamers): 7.65 (d,J=8.4 Hz, 2H), 7.64 (d, J=9.3 Hz, 2H), 7.58 (d, J=10.5 Hz, 2H), 7.55 (d,J=8.5 Hz, 2H), 4.94 (s, 2H), 4.78 (s, 2H), 4.08 (t, J=5.9 Hz, 2H), 3.90(t, J=5.8 Hz, 2H), 3.02 (t, J=5.8 Hz, 2H), 2.96 (t, J=5.9 Hz, 2H), 2.36(s, 3H), 2.31 (s, 3H).

B.1-[3-(4-Chloro-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

To a stirred solution of 1.00 g (3.63 mmol) of1-[3-(4-chloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneand 2.85 mL (36.3 mmol) of epichlorohydrin was added 1.30 g (3.99 mmol)of solid Cs₂CO₃. The reaction was stirred for 48 h and the solvent wasremoved under reduced pressure. The residue was then diluted with H₂O(50 mL) and EtOAc (50 mL). The layers were separated, and the organiclayer was washed with H₂O (25 mL) and brine (25 mL), dried over Na₂SO₄and the solvent was removed under reduced pressure. Purification byflash chromatography (silica, 0-15% acetone/CH₂Cl₂) afforded 0.72 g(60%) of a white solid. TLC (silica, 5% MeOH/CH₂Cl₂): R_(f)=0.5. MS(electrospray): m/z calculated for C₁₇H₁₈ClN₃O₂ [M+H]⁺, 332.11, observed332.0. ¹H NMR (400 MHz, CDCl₃, a mixture of amide rotamers): 7.60 (d,J=8.6 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.6 Hz, 2H), 7.36 (d,J=8.4 Hz, 2H), 4.80 and 4.73 (A and B of AB quartet, J_(ab)=15.8 Hz,2H), 4.60 (s, 2H), 4.47 (dd, J=15.3, 2.5 Hz, 1H), 4.42 (dd, J=15.0, 2.7Hz, 1H), 4.11 (dd, J=5.3, 2.5 Hz, 1H), 4.08 (dd, J=5.1, 3.3 Hz, 1H),3.99-3.85 (m, 2H), 3.73 (dt, J=5.9, 1.8 Hz, 2H), 3.37 (m, 2H), 2.87-2.80(m, 3H), 2.80-2.69 (m, 3H), 2.53 (dd, J=4.7, 2.5 Hz, 1H), 2.48 (dd,J=4.6, 2.6, 1H), 2.19 (s, 3H), 2.15 (s, 3H).

C.1-{3-(4-Chloro-phenyl)-1-[3-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-2-hydroxy-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanone

To a stirred solution of 3.20 g (9.64 mmol) of1-[3-(4-chloro-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneand 2.07 g (14.5 mmol) of 1,4-dioxa-8-azaspiro[4.5]decane in CH₂Cl₂ (65mL) was added 1.79 g (2.89 mmol) of Yb(OTf)₃.H₂O. The reaction wasstirred overnight and was then directly purified by flash chromatography(silica, 0-5% MeOH/CH₂Cl₂) to afford 3.70 g (81%) of the title compound.TLC (silica, 5% MeOH/CH₂Cl₂): R_(f)=0.35. MS (electrospray),m/zcalculated for C₂₄H₃₁ClN₄O₄ [M⁺+H], 475.20, observed 475.1.

D.1-{3-[5-Acetyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-one

A suspension of 0.50 g (0.96 mmol) of1-{3-(4-chloro-phenyl)-1-[3-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-2-hydroxy-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanonein 1 N HCl (2.0 mL) was heated to 65° C. for 48 h in a sealed vessel.The reaction was allowed to cool to room temperature and was dilutedwith CHCl₃ (20 mL) and saturated NaHCO₃ (20 mL). The aqueous phase wasextracted with CHCl₃ (2×10 mL) and the combined organic extracts weredried over Na₂SO₄ and the solvent was removed under reduced pressure.The crude material was then diluted with Ac₂O (3.0 mL) and was stirredfor 48 h. The solvent was removed under reduced pressure and the crudematerial was pumped down overnight. The resulting solid was dissolved inMeOH (5.0 mL) and a catalytic amount (0.05 g) of K₂CO₃ was added to themixture and stirring was continued overnight. The reaction was thendiluted with H₂O (20 mL) and CH₂Cl₂ (20 mL) and the layers wereseparated. The aqueous phase was extracted with CH₂Cl₂ (2×10 mL) and thecombined organic extracts were dried over Na₂SO₄ and the solvent wasremoved under reduced pressure. Purification by flash chromatography(silica, 0-10% MeOH/CH₂Cl₂) afforded 0.29 g (65% over 3 steps) of awhite solid. TLC (silica, 5% MeOH/CH₂Cl₂): R_(f)=0.35. MS(electrospray); m/z calculated for C₂₂H₂₇ClN₄O₃, [M+H]⁺, 431.18,observed 431.1. ¹H NMR (400 MHz, CDCl₃, a mixture of amide rotamers):7.59 (d, J=8.3 Hz, 1H), 7.53 (d, J=8.6 Hz, 1H), 7.41 (d, J=8.5 Hz, 1H),7.37 (d, J=8.5 Hz, 1H), 4.85 and 4.73 (A and B of AB quartet,J_(ab)=15.8 Hz, 1H), 4.62 (s, 1H), 4.26-4.12 (m, 2H), 4.09-3.68 (m, 4H),3.49 (s, 1.5H), 3.28 (s, 1.5H).

E.2-(1-{3-[5-Acetyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl]-piperidin-4-ylamino)-benzonitrile

To a stirred solution of 50.0 mg (116.0 μmol) of5-1-{3-[5-acetyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-oneand 9.6 mg (82.5 μmol) of 2-aminobenzonitrile in AcOH (0.5 mL) was added130.0 mg (917.0 μmol) Na₂SO₄ and the reaction was allowed to stir for 1h. To this mixture was added 58.0 mg (275.0 tmol) NaBH(OAc)₃ and thereaction was stirred for 48 h. The mixture was diluted with CH₂Cl₂ (20mL) and saturated NaHCO₃ (20 mL). The aqueous phase was extracted withCH₂Cl₂ (2×10 mL) and the combined organic extracts were dried overNa₂SO₄ and the solvent was removed under reduced pressure. Purificationby flash chromatography (silica, 0-5% MeOH/CH₂Cl₂) afforded 9.0 mg (20%)of a white solid. TLC (silica, 5% MeOH/CH₂Cl₂): R_(f)=0.2. MS(electrospray): m/z calculated for C₂₉H₃₃ClN₆O₂, [M+H]⁺, 533.24,observed 533.3. ¹H NMR (400 MHz, CDCl₃, a mixture of amide rotamers):7.58 (d, J=8.6 Hz,1H), 7.52 (d, J=8.4 Hz,1H), 7.43-7.34 (m, 4H), 6.69(dt, J=7.6, 4.0 Hz,1H), 6.64 (d, J=8.6 Hz, 1H), 4.83 and 4.73 (A and Bof AB quartet, J_(ab)=15.7 Hz, 1H), 4.61 (s, 1H), 4.44 (d, J=7.3 Hz,1H), 4.33-4.14 (m, 2H), 4.11-3.84 (m, 2H), 3.83-3.67 (m, 1H), 3.55-3.43(m,1H), 3.17-2.94 (m,1H), 2.93-2.75 (m, 2H), 2.74-2.54 (m, 2H), 2.21 (s,1.5H), 2.16 (s, 1.5H), 2.23-1.53 (m, 9H).

Example 2

1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-oneA.1-[3-(4-Trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone.

A solution of N-acetyl-4-piperidone (2.82 g, 20 mmol), morpholine (1.93mL, 22 mmol) and ptoluenesulfonic acid (5 mg) in benzene (8.5 mL) wasrefluxed for 8 h in a Dean-Stark apparatus. The solvent was removed andthe residue dissolved in CH₂Cl₂ (20 mL). Triethylamine (3.1 mL) wasadded and p-trifluoromethylbenzoyl chloride (3.27 mL, 22 mmol) in CH₂Cl₂(4 mL) was added dropwise into the solution at 0° C. The reactionmixture was stirred at 25° C. for 24 h and diluted with aqueous HCl (5%,25 mL). After stirring for another 30 min, the organic layer wasseparated, washed with H₂O (20 mL), dried (Na₂SO₄), and concentrated.The residue was dissolved in EtOH (95%, 18 mL) and treated at 0° C withhydrazine (2.9 mL, 60 mmol). The mixture was stirred at 25° C. for 3 hand H₂O (4 mL) was added. Most of the volatiles were removed and theresidue extracted with CH₂Cl₂ (50 mL). The organic layer was separated,washed with H₂O (20 mL), dried over Na₂SO₄, and concentrated. Columnchromatography (silica, 5% MeOH/CH₂Cl₂) provided 5.1 g (83%) of a whitepowder. TLC (silica, 10% MeOH/CH₂Cl₂): R_(f)=0.30. MS (electrospray):m/z 332.0 ([M+Na]⁺, C₁₅H₁₄F₃N₃O requires 309.1). ¹H NMR (CDCl₃, 400 MHz,a mixture of two rotamers): 7.73-7.67 (m, 4H), 4.85 (s, 1.2H), 4.68 (s,0.8H), 3.96 (t, J=4.5 Hz, 0.8H), 3.78 (t, J=4.5 Hz, 1.2H), 2.89 (t,J=4.5 Hz, 1.2H), 2.83 (t, J=4.5 Hz, 0.8H), 2.23 (s, 1.8H), 2.18 (s,1.2H).

B.1-[1-Oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

A solution of1-[3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone(2.4 g, 7.77 mmol) in DMF (15 mL) was treated with cesium carbonate(5.05 g, 15.5 mmol) and epichlorohydrin (6.1 mL, 77.7 mmol) at 25° C.and stirred for 24 h before it was diluted with EtOAc (100 mL) and H₂O(50 mL). The organic layer was separated, washed with H₂O (2×50 mL),brine (50 mL), dried over Na₂SO₄, and concentrated. Columnchromatography (silica, 10% acetone/CH₂Cl₂) provided 2.30 g (81%) of awhite powder. TLC (silica, 10% MeOH/CH₂Cl₂): R_(f)=0.35. MS(electrospray): m/z 388.0 ([M+Na]⁺, C₁₈H₁₈F₃N₃O₂ requires 365.1). ¹H NMR(CDCl₃, 400 MHz, a mixture of two rotamers): 7.77 and 7.63 (AB pattern,J_(ab)=8.2 Hz, 2H), 7.71 and 7.67 (AB pattern, J_(ab)=8.4 Hz, 2H), 4.82and 4.76 (AB pattern, J_(ab)=15.5 Hz, 1.2H), 4.58 (s, 0.8H), 4.45-4.35(m, 1H), 4.08-4.02 (m, 1H), 3.92-3.80 (m, 1H), 3.70-3.63 (m, 1H), 3.30(m, 1H), 2.80-2.67 (m, 3H), 2.48-2.42 (m, 1H), 2.13 (s, 1.3H), 2.08 (s,1.7H).

C.1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4.3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one

A solution of1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone(1.17 g, 3.2 mmol) in DMF (10 mL) was treated with ytterbium(III)triflate (0.4 g, 0.64 mmol) and 4-(2-keto-1-benzimidazolinyl)piperidine(1.04 g, 4.8 mmol) at 25° C. and stirred for 48 h before it was dilutedwith CH₂Cl₂ (100 mL) and H₂O (50 mL). The organic layer was separated,washed with H₂O (2×50 mL), dried over Na₂SO₄, and concentrated. Flashcolumn chromatography (silica, 5% MeOH/CH₂Cl₂) afforded 1.71 g (92%) ofa white powder. TLC (silica, 10% MeOH/CH₂Cl₂): R_(f)=0.25. MS(electrospray): m/z 583.5 ([M+H]⁺, C₃₀H₃₃F₃N₆O₃ requires 582.3). ¹H NMR(CDCl₃, 400 MHz, a mixture of two rotamers): 9.30 (br s, 0.5H), 9.25 (brS, 0.5H), 7.82 and 7.68 (AB pattern, J_(ab)=8.2 Hz, 2H), 7.76 and 7.72(AB pattern, J_(ab)=8.4 Hz, 2H), 7.25-7.05 (m, 4H), 4.92 and 4.80 (ABpattern, J_(ab)=15.6 Hz, 1.1H), 4.70 (s, 0.9H), 4.40-3.70 (m, 7H),3.20-2.82 (m, 4H), 2.60-2.45 (m, 4H), 2.35-2.25 (m, 1H), 2.25 (s, 1.5H),2.20 (s, 1.5H), 1.90-1.87 (m, 2H).

Example 3

3-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3H-benzooxazol-2-oneA.1-[3-(4-Bromo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

A flask equipped with a Dean-Stark trap, was charged withN-acetyl-4-piperidone (100.1 g, 709 mmol), piperidine (68 mL, 779 mmol),pTsOH (3.7 g) and benzene (500 mL). The mixture was heated to 125° C.After 17 h the mixture was allowed to cool and divided into twoportions. A solution of p-bromobenzoyl chloride (70.0 g, 319 mmol) inCH₂Cl₂ (400 mL) was added dropwise to a 0° C solution of the enamine(ca. 355 mmol) in CH₂Cl₂ (320 mL) over 15 h. The mixture was thenallowed to warm to 23° C. and stirred for an additional 5 h. Thesolution was treated with 1 N HCl (500 mL) and stirred vigorously for1.5 h. The layers were separated and the aqueous layer was extractedwith CH₂Cl₂ (2×300 mL). The combined extracts were washed with sat.aqueous NaHCO₃ (300 mL), H₂O (300 mL), brine (300 mL), dried over Na₂SO₄and concentrated. The residue was dissolved in MeOH (300 mL) and treatedwith NH₂NH₂ (50.0 mL, 1.59 mol). The mixture was stirred for 17 h beforethe precipitate formed was collected by filtration and air dried to give52 g (50%) of the title compound which was suitable for use withoutfurther purification. TLC (silica, 5% MeOH/CH₂Cl₂): R_(f)=0.3. MS(electrospray): m/z calculated for C₁₄H₁₅ ⁷⁹BrN₃O [M+H]⁺, 320.04, found320. ¹H NMR (CD₃OD/CDCl₃, 400 MHz, a mixture of amide rotamers): 7.53and 7.35 (A and B of AA′BB′, J=8.5 Hz, 2H), 7.51 and 7.39 (A and B ofAA′BB′, J=8.6 Hz, 2H), 4.72 (s, 2H), 4.58 (s, 2H), 3.85 (t, J=5.9 Hz,2H), 3.71 (t, J=5.8 Hz, 2.81, (t, J=5.8 Hz, 2H), 2.74, (t, J=5.8 Hz,2H), 2.16 (s, 3H), 2.11 (s, 3H).

B.1-[3-(4-Bromo-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

Cs₂CO₃ (11.58 g, 35.5 mmol) was added to a solution of1-[3-(4-bromo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone(7.59 g, 23.7 mmol) and epichlorohydrin (20 mL, 234 mmol) in DMF (100mL). The mixture was stirred for 18 h then diluted with EtOAc (800 mL)and washed with saturated aqueous NaHCO₃ (2×100 mL), H₂O (2×100 mL), andbrine (100 mL). The NaHCO₃ layer was extracted with EtOAc (2×150 mL).The combined washes were extracted with EtOAc (2×100 mL). The combinedextracts were dried over Na₂SO₄ and concentrated. Column chromatography(silica, 10-20% acetone/CH₂Cl₂) afforded 4.98 g (56%) of the titlecompound. HPLC (reverse phase conditions), t_(R)=4.90 min. MS(electrospray): m/z calculated for C₁₇H₁₉ ⁷⁹BrN₃O₂, [M+H]⁺, 376.07,found 376.0. ¹H NMR (CDCl₃, 400 MHz, a mixture of amide rotamers): 7.47(d with fine splittings, J=8.5, Hz, 2H), 7.44 (m, 4H), 7.38 (d with finesplittings, J=8.5, Hz, 2H), 4.71 and 4.64 (A and B of AB quartet,J_(ab)=15.7 Hz, 2H), 4.51 (s, 2H), 4.39 (dd, J=15.1, 2.5 Hz, 1H), 4.34(dd, J=15.0, 2.9 Hz, 1H), 4.02 (dd, J=5.2, 3.9 Hz, 1H), 3.98 (dd, J=5.3,3.7 Hz, 1H), 3.83 (m, 2H), 3.64 (m, 2H), 3.25 (br m, 2H), 2.80-2.60 (m,6H), 2.46 (dd, J=4.6, 2.6 Hz, 1H), 2.38 (dd, J=4.6, 2.6 Hz, 1H), 2.10(s, 3H), 2.06 (s, 3H).

C. 4-(2-Oxo-benzooxazol-3-yl)-piperidine-1-carboxylic acid tert-butylester

To a stirred solution of 1.00 g (5.01 mmol) of tert-butyl4-oxo-1-piperidinecarboxylate and 0.55 g (5.01 mmol) of 2-aminophenol inCH₂Cl₂ (15 mL) under nitrogen at rt was added 1.62 g (7.52 mmol) ofNaBH(OAc)₃ in one portion and the mixture was stirred for 14 h. Themixture was diluted with CH₂Cl₂ (50 mL) and saturated NaHCO₃ (75 mL) andthe layers were separated. The aqueous layer was extracted with CH₂Cl₂(2×25 mL) and the combined organic layers were washed with brine, driedover Na₂SO₄, and the solvent was removed under reduced pressure. Thecrude solid was diluted with CH₂Cl₂ (15 mL) and 0.89 g (5.51 mmol) ofcarbonyldiimidazole was added in one portion and mixture was stirred for16 h. The mixture was diluted with CH₂Cl₂ (50 mL) and 1 N HCl (50 mL)and the layers were separated. The aqueous layer was extracted withCH₂Cl₂ (2×25 mL) and the combined organic layers were washed with brine,dried over Na₂SO₄, and the solvent was removed under reduced pressure.Flash chromatography (silica, 0-5% acetone/CH₂Cl₂) afforded 1.59 g (99%)of a white solid. TLC (silica, 5% acetone/CH₂Cl₂): R_(f)=0.6. MS(electrospray): m/z calculated for C₁₇H₂₂N₂O₄, [M+Na]+, 341.1, observed341.1.

D. 3-Piperidin-4-yl-3H-benzooxazol-2-one

To a stirred solution of 1.00 g (2.87 mmol) of4-(2-oxo-benzooxazol-3-yl)-piperidine-1-carboxylic acid tert-butyl esterin CH₂Cl₂ (6.0 mL) was added TFA (6.0 mL) and the mixture was stirredfor 12 h. The solvents were removed under reduced pressure and the crudesolid was diluted in MeOH (10 mL) and saturated NaHCO₃ (15 mL) was addedto the mixture and stirring was continued for 10 min. The solution wasdiluted with CH₂Cl₂ (30 mL) and the layers were separated. The aqueousphase was extracted with CH₂Cl₂ (2×20 mL) and the organic layers werecombined, dried over Na₂SO₄ and the solvent was removed under reducedpressure to afford 1.02 g (88%) of a pale yellow solid. TLC (silica, 10%MeOH/CH₂Cl₂): R_(f)=0.1. MS (electrospray): m/z calculated forC₁₂H₁₄N₂O₂, [M+H]⁺, 219.11, observed 219.1.

E.3-(1-{3-[5Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl-2-hydroxy-propyl]-piperidin-4-yl)-3H-benzooxazol-2-one

To a stirred mixture of 0.025 g (0.066 mmol) of3-piperidin-4-yl-3H-benzooxazol-2-one and 0.015 g (0.066 mmol) of1-[3-(4-bromo-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanonein EtOH (0.5 mL) was added 0.01 mL (0.066 mmol) of Et₃N. The mixture washeated to 80° C in a sealed vessel for 16 h. The reaction was cooled andthe solvent was removed under reduced pressure. Flash chromatography(silica, 0-5% MeOH/CH₂Cl₂) afforded 0.030 g (79%) of a white foam. TLC(silica, 5% MeOH/CH₂Cl₂): R_(f)=0.4. MS (electrospray): m/zcalculatedfor C₂₉H₃₂BrN₅O₄, [M+H]⁺, 594.16, observed 594.2. ¹H NMR (400 MHz,CDCl₃, a mixture of amide rotamers): 7.60-7.43 (m, 4H), 7.23-7.06 (m,4H), 4.83 and 4.73 (A and B of AB quartet, J_(ab)=15.4 Hz, 1H), 4.61 (s,1H), 4.38-3.66 (m, 7H), 3.37-3.02 (m, 2H), 2.99-2.28 (m, 6H), 2.21 (s,1.5H), 2.16 (s, 1.5H), 1.99-1.83 (m, 3H).

Example 4

1-(3-(4-Chloro-3-methyl-phenyl)-1-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneA.1-[3-(4-Chloro-3-methyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

To a stirred solution of 1-acetyl-4-piperidone (3 g, 0.021 mol) andmorpholine (1.86 g, 0.21 mol) in benzene (21 mL) was added a catalyticamount (˜0.015 g) of p-toluenesulfonic acid. The mixture was heated toreflux for 10 h under a Dean-Stark trap. The solvent was removed underreduced pressure to give a brown oil. The crude product was diluted withCH₂Cl₂ (10.5 mL), and Et₃N (3.0 mL, 0.021 mol) was added. The mixturewas cooled to 0° C, and a solution of 3-methyl-4-chlorobenzoyl chloride(2.7 mL, 0.021 mol) in CH₂Cl₂ (3.0 mL) was added slowly by droppingfunnel over 1 h. The mixture was allowed to warm to room temperature andstir overnight. The reaction mixture was then diluted with 1 N HCl (9.0mL) and stirred vigorously for 3 h. The aqueous layer was extracted withCH₂Cl₂ (3×15 mL). The combined extracts were dried over Na₂SO₄, and thesolvent was removed under reduced pressure. The crude oil was dilutedwith EtOH (21 mL) and cooled to 0° C. To this stirred solution wasslowly added hydrazine (2.0 mL, 0.064 mol), and the mixture was allowedto warm to room temperature and stir overnight, during which time awhite precipitate formed. The volume of the reaction mixture was reducedto ˜9 mL, and EtOAc (45 mL) was added. The suspension was stirredvigorously for 2 h and was filtered then washed with EtOAc (2×12 mL) anddried under vacuum to afford 4.93 g (81% over 3 steps) of a pale yellowsolid. TLC (silica, 10% acetone/CH₂Cl₂): R_(f)=0.2. MS (electrospray):exact mass calculated for C₁₅H₁₆ClN₃O, 289.10; m/zfound, 290.1 [M⁺+H].

B.1-[3-(4-Chloro-3-methyl-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

Cs₂CO₃ (11 g, 33.8 mmol) was added to a solution of1-[3-(4-chloro-3-methyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone(4.9 g, 16.9 mmol) in DMF (49 mL), which was then stirred for 15 min.Epichlorohydrin (13.2 mL, 169 mmol) was added, and the mixture wasstirred under N₂ at room temperature for 16 h. EtOAc (250 mL) was addedto the reaction mixture, which was then stirred for 5 min. The resultingsolution was washed with water (2×50 mL) and brine (1×50 mL). Theorganic extracts were dried over Na₂SO₄ and concentrated. The residuewas purified by column chromatography (silica, 10-20% acetone/CH₂Cl₂) toobtain 3.8 g (65%) of a white solid. TLC (silica, 10% acetone/CH₂Cl₂):R_(f)=0.3. MS (electrospray): exact mass calculated for C₁₈H₂₀ClN₃O₂,345.12; m/zfound, 346.1 [M⁺+H], 368.0 [M⁺+Na],

C. 4-(3,4-Dichlorophenoxy)-piperidinium trifluoroacetate

A suspension of 0.69 g (20.0 mmol) of triphenylphosphine (polymersupported, 3 mmol P/g) in CH₂Cl₂ (4.0 mL) was stirred for 15 min toswell the resin. To this suspension was added 0.20 g (1.00 mmol) of1-tert-butoxycarbonyl-4-piperidinol, 0.16 g (1.00 mmol) of3,4-dichlorophenol, and 0.35 g (1.50 mmol) of di-tert-butylazodicarboxylate. The reaction was stirred for 4 h and was filtered andthe resin was washed with 5% MeOH/CH₂Cl₂ (2×20 mL) and Et₂O (20 mL). Theorganic layers were combined and the solvent was removed. The crude oilwas diluted with CH₂Cl₂ (2.0 mL) and TFA (2.0 mL) and the mixture wasstirred overnight. The solvent was removed under reduced pressure toafford the crude TFA salt which was used without further purification.TLC (silica, 10% MeOH/CH₂Cl₂): R_(f)=0.1. MS (electrospray): m/zcalculated for C₁₁H₁₃Cl₂NO, [M+H]⁺, 246.04, observed 246.1.

D.1-(3-(4-Chloro-3-methyl-phenyl)-1-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-Propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone

To a stirred solution of 25.0 mg (0.066 mmol) of1-[3-(4-chloro-3-methyl-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneand 25.0 mg (0.10 mmol) of 4-(3,4-dichlorophenoxy)-piperidiniumtrifluoroacetate in EtOH (0.5 mL) was added 0.019 mL (0.014 mmol) ofEt₃N. The mixture was heated to 80° C in a sealed vessel for 16 h. Thereaction was cooled and the solvent was removed under reduced pressure.Flash chromatography (0-5% MeOH/CH₂Cl₂) afforded 28 mg (74%) of a paleyellow foam. TLC (silica, 5% MeOH/CH₂Cl₂): R_(f)=0.5. MS (electrospray):m/z calculated for C₂₉H₃₃Cl₃N₄O₃, [M+H]⁺, 591.16, observed 591.2. ¹H NMR(400 MHz, CDCl₃, a mixture of amide rotamers): 7.51 (d, J=6.9 Hz, 1H),7.41-7.29 (m, 3H), 6.99 (d, J=2.9 Hz,1H), 6.74 (dd, J=9.0, 3.1 Hz, 1H),4.82 and 4.73 (A and B of AB quartet, J_(ab)=15.7 Hz, 1H), 4.60 (s, 1H),4.46-3.93 (m, 4H), 3.92-3.83 (m, 1H), 3.82-3.68 (m, 1H), 3.08-2.51 (m,6H), 2.43 (s, 1.5H), 2.41 (s, 1.5H), 2.21 (s, 1.5H), 2.15 (s, 1.5H)2.00-1.83 (m, 3H), 1.75-1.39 (m, 4H).

Example 5

1-(3-(4-Chloro-3-methyl-phenyl)-1-{3-[4-(2,3-dihydro-indol-1-yl)-piperidin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneA. 1-Piperidin-4-yl-2,3-dihydro-1H-indole

Indoline (11.0 g, 92 mmol) and N-BOC-4-piperidone (18.4 g, 92 mmol) wereset stirring in 300 mL of CH₂Cl₂ under an atmosphere of nitrogen at rt.Acetic acid (5.5 mL, 96 mmol) was then added. After 1.5 h sodiumtriacetoxyborohydride (27.4 g, 129 mmol) was added and the mixture wasleft stirring for 4 days. The mixture was quenched by the slow additionof saturated NaHCO₃. The organics were separated, dried (MgSO₄) and thesolvent was evaporated under reduced pressure to give 28 g (100%) of aclear dark green liquid. The crude material was brought up in 1:1TFA/CH₂Cl₂ (100 mL) and stirred at room temperature. After 45 min thesolvent was evaporated under reduced pressure, the oil brought up inEtOAc, and cooled on ice to form a beige precipitate. The solid wasfiltered, washed with Et₂O and air dried to give 22.5 g (57%) of a whitesolid as a TFA salt. MS (electrospray): exact mass calculated forC₁₃H₁₈N₂, 202.15; m/zfound, 203.2. ¹H NMR (400 MHz, DMSO-d₆): 8.74 (brs, 1H), 8.46 (br s, 1H), 7.07 (m, 2H), 6.63 (m, 2H), 3.81 (br s, 1H),3.46 (m, 2H), 3.37 (m, 2H), 3.12 (m, 2H), 2.95 (m, 2H), 1.86 (m, 4H).

B.1-(3-(4-Chloro-3-methyl-phenyl)-1-{3-[4-(2,3-dihydro-indol-1-yl)-piperidin-1-yl]-2-hydroxy-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone

1-Piperidin-4-yl-2,3-dihydro-1H-indole (TFA salt) (506 mg, 1.18 mmol)and1-[3-(4-chloro-3-methyl-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone(261 mg, 0.75 mmol) were set stirring in 20 mL of EtOH and heated to 80°C. After 20 h the mixture was cooled, evaporated, brought up in EtOAcand washed with saturated NaHCO₃. The organics were dried (MgSO₄) andevaporated to give a clear golden oil. Flash chromatography (silica,100% acetone) gave 260 mg (63%) of a white solid. TLC (silica, 100%acetone): R_(f)=0.10. MS (electrospray): exact mass calculated forC₃₁H₂₈ClN₅O₂, 547.27; m/zfound, 548.3. ¹H NMR 400 MHz,CDCl₃): 7.64 (m,1H), 7.43 (m, 2H), 7.16 (m, 2H), 6.72 (s, 1H), 6.50 (m, 1H), 4.88 (m,1H), 4.73 (s, 1H), 4.28 (m, 2H), 4.13 (m, 2H), 3.92 (m, 2H), 3.47 (m,3H), 30.9 (m, 6H), 2.55 (m, 6H), 2.27 (m, 3H), 1.84 (m, 4H). Example 6

(S)-1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihydro-benzoimidazol-2-oneA.(R)-1-[3-(4-Chloro-3-methyl-phenyl)-1-(2,3-dihydroxy-propyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

A solution of KHMDS (0.5 M, 8.4 mL, 4.1 mmol) was added to a solution of1-[3-(4-chloro-3-methyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone(1.01 g, 3.49 mmol) in DMF (8.5 mL). The mixture was stirred for 1 hthen (2R)-1-tert-butyldimethylsilylglycidol (1.97 g, 10.5 mmol) wasadded. The mixture was stirred for 17 h then partitioned between EtOAc(500 mL) and saturated aqueous NaHCO₃ (100 mL). The EtOAc layer waswashed with H₂O (3×100 mL), and brine (100 mL). The combined washes wereextracted with EtOAc (2×100 mL). The combined extracts were dried overNa₂SO₄ and concentrated. The residue was dissolved in MeOH (50 mL) andtreated with CSA (171 mg). The resulting mixture was stirred for 24 hthen concentrated to near dryness. The residue was diluted with EtOAc(300 mL), washed with NaHCO₃ (100 mL), dried over Na₂SO₄ andconcentrated. Flash chromatography (silica, 5-10% MeOH/CH₂Cl₂) provided652 mg (50%) of the non-racemic diol. TLC (silica, 10% MeOH/CH₂Cl₂):R_(f)=0.2. MS (electrospray): mlz calculated for C₁₈H₂₃ ³⁵ClN₃O₃([M+H]⁺, 364.14, found 364.1.

B.(R)-1-[3-(4-Chloro-3-methyl-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-Pyrazolo[4,3-c]pyridin-5-yl]-ethanone

(R)-1-[3-(4-Chloro-3-methyl-phenyl)-1-(2,3-dihydroxy-propyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone(452 mg, 1.24 mmol) and pyridinium p-toluenesulfonate (85 mg) werecombined in MeC(OMe)₃ (50 mL) and briefly sonicated. The mixture wasstirred for 17 h, concentrated, and the residue dissolved in CH₂Cl₂ (8mL). The solution was cooled to 0° C. and treated with AcBr (0.15 mL,2.0 mmol). After 5 h the mixture was partitioned between EtOAc (300 mL)and saturated aqueous NaHCO₃ (75 mL). The EtOAc layer was washed withH₂O (75 mL) and brine (75 mL), dried over Na₂SO₄ and concentrated. Theresidue was combined with K₂CO₃ (243 mg, 1.84 mmol) in MeOH (50 mL) andstirred for 3 h then worked up as described above. Purification bycolumn chromatography (silica, 10-40% acetone/CH₂Cl₂) gave 159 mg (37%)of the title compound. Chiral HPLC (Daicel OD, 0.5% Et₂NH/MeOH) analysisindicated >95% optical purity. HPLC (reverse phase conditions),t_(R)=4.97 min. MS (electrospray): exact mass calculated forC₁₈H₂₀ClN₃O₂ [M⁺+Na], 368.11; m/z found 368.05. ¹H NMR (CDCl₃, 400 MHz,a mixture of amide rotamers): 7.54 (br d, J=6.3 Hz, 2H), 7.41-7.35 (m,3H), 7.29 (dd, J=8.2, 1.9 Hz, 1H), 4.81 and 4.74 (A and B of AB quartet,J_(ab)=15.7 Hz, 2H), 4.60 (s, 2H), 4.48 (dd, J=15.2, 2.4 Hz, 1H), 4.42(dd, J=15.4, 2.8 Hz, 1H), 4.13 (t, J=4.7 Hz, 1H), 4.09 (dd, J=4.6 Hz,1H), 3.93 (m, 2H), 3.74 (t, J=5.8 Hz, 1H), 3.73 (t, J=5.8 Hz, 1H), 3.34(m, 2H), 2.85-2.75 (m, 6H), 2.53 (dd, J=4.6, 2.5 Hz, 1H), 2.48 (dd,J=4.6, 2.6 Hz, 1H), 2.43 (s, 3H), 2.41 (s, 3H), 2.20 (s, 3H), 2.15 (s,3H).

C. 4-(5-Chloro-2-nitro-phenylamino)-piperidine-1-carboxylic acid ethylester

To a solution of 2.03 g (11.6 mmol) of 4-chloro-2-fluoro-nitrobenzene inDMF (12.0 mL) at rt was added 2.00 g (11.6 mmol) of ethyl4-amino-1-piperidinecarboxylate. A yellow precipitate formed within 30min and the reaction was further diluted with DMF (12.0 mL) and CH₂Cl₂(5.0 mL) and was shaken at 300 RPM overnight. The solvent was removedunder reduced pressure and the resulting solid was dried under vacuum.The crude product was purified by flash chromatography (silica, 0-5%MeOH/CH₂Cl₂) to afford 2.83 g (81%) of the title compound. TLC (silica,5% MeOH/CH₂Cl₂): R^(f)=0.4. MS (electrospray): m/z calculated forC₁₄H₁₈ClN₃O₄ [M⁺+Na] 350.09, observed 350.0. ¹H NMR (400 MHz, CDCl₃):8.13 (apparent d, J=9.1 Hz, 2H), 6.84 (d, J=2.0 Hz, 1H), 6.62 (dd,J=9.4, 2.3 Hz, 1H), 4.15 (q, J=14.9, 7.3 Hz, 2H), 4.08 (br d, J=12.4 Hz,2H), 3.70-3.58 (m, 1H), 3.17-3.05 (m, 2H), 2.07 (br dd, J=13.1, 3.1 Hz,2H), 1.63-1.50 (m, 2H), 1.28 (t, J=7.0 Hz, 3H).

D.4-(6-Chloro-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylicacid ethyl ester

To a stirred solution of 0.50 g (1.52 mmol) of4-(5-chloro-2-nitro-phenylamino)-piperidine-1-carboxylic acid ethylester in EtOH (15.0 mL) was added concentrated HCl (3.0 mL) followed by0.99 g (15.2 mmol) of zinc powder. After 1 h, additional concentratedHCl (1.5 mL) followed by 0.99 g (15.2 mmol) of zinc powder was added andthe reaction was stirred for 1.5 h. The mixture was filtered through apad of celite and was washed with 5% MeOH/CH₂Cl₂. The mixture wasdiluted with saturated NaHCO₃ and a precipitate formed. The layers wereseparated and the aqueous phase was extracted (3×5% MeOH/CH₂Cl₂). Thecombined organic layers were dried over Na₂SO₄ and the solvent wasremoved under reduced pressure to afford a brown oil. The crude oil wasdiluted with CH₂Cl₂ (15.0 mL) and 0.64 mL (4.56 mmol) of Et₃N was addedfollowed by 0.45 g (1.52 mmrol) of triphosgene. The reaction was allowedto stir overnight and was then diluted with 1 N NaOH (20 mL) and stirredfor an additional 1 h. The layers were separated and the aqueous phasewas extracted with CH₂Cl₂ (3×20 mL). The combined organic extracts weredried over Na₂SO₄ and the solvent was removed under reduced pressure.Purification by flash chromatography (silica, 0-5% MeOH/CH₂Cl₂) afforded0.33 g (67% over 2 steps) of the title compound. TLC (silica, 5%MeOH/CH₂Cl₂): R_(f)=0.5. MS (electrospray): m/z calculated forC₁₅H₁₈ClN₃O₃ [M⁺+Na] 346.10, observed 346.0. ¹H NMR (400 MHz, CDCl₃):9.41 (s, 1H), 7.11 (d, J=2.0 Hz, 1H), 7.04 (d, J=1.8 Hz, 1H), 7.02 (s,1H), 4.48-4.33 (m, 3H), 4.20 (q, J=7.1 Hz, 2H), 2.92 (t, J=12.5 Hz, 2H),2.30 (dq, J=12.9, 4.6 Hz, 2H), 2.10 (d, J=12.6 Hz, 2H), 1.31 (t, J=7.1Hz, 3H).

E. 6-Chloro-1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one

A suspension of 0.20 g (0.62 mmol) of4-(6-chloro-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylicacid ethyl ester in 10% NaOH (0.62 mL) was heated to 105° C. for 6 h andthen cooled. The solution was adjusted to pH 1 (conc. HCl) and then backto pH 10 (NaOH). Then, the mixture was diluted with 5% MeOH/CH₂Cl₂ (˜30mL) until both layers were clear. The layers were separated and theaqueous phase was extracted with 5% MeOH/CH₂Cl₂ (2×30 mL). The combinedorganic layers were dried over Na₂SO₄ and the solvent was removed underreduced pressure to afford 0.12 g (76%) of a light brown solid. TLC(silica, 10% MeOH/CH₂Cl₂): R_(f)=0.1. MS (electrospray): m/z calculatedfor C₁₂H₁₄ClN₃O [M⁺+H] 252.08, observed 252.1. ¹H NMR (400 MHz, CDCl₃):7.27 (d, J=1.6 Hz, 2H), 7.02 (d, J=1.6 Hz, 1H), 7.01 (s, 1H), 4.38 (m,1H), 3.30 (br d, J=11.9 Hz, 2H), 2.82 (dt, J=12.3, 2.0 Hz, 2H ), 2.35(dq, J=12.3, 3.5 Hz, 2H), 1.85 (br dd, J=12.1, 2.1 Hz, 2H).

F.(S)-1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl]-piperidin-4-yl)-6-chloro-1,3-dihydro-benzoimidazol-2-one

(R)-1-[3-(4-Chloro-3-methyl-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone(31 mg, 0.10 mmol) and6-chloro-1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (36 mg, 0.17mmol) were combined in EtOH (0.3 mL) and heated to 70° C. After 18 h themixture was allowed to cool, diluted with CH₂Cl₂ and purified bypreparative TLC (silica, 8% MeOH/CH₂Cl₂) to give 7 mg (12%) of the titlecompound. HPLC (reverse phase conditions), t_(R)=3.49 min. MS(electrospray): m/z calculated for C₃₀H₃₅ ³⁵Cl₂N₆O₃ [M⁺+H] 597.22, found597.20. ¹H NMR (CDCl₃, 400 MHz, a mixture of amide rotamers): 9.16 (brd, J=10.1 Hz, 1H), 7.55 (br m, 1H), 7.40-7.28 (m, 2H), 7.18 (br s, 1H),7.03 and 6.98 (A and B of ABX (with fine splittings), J_(ab)=8.4 Hz,2H), 4.85 and 4.74 (A and B of ABX (with fine splittings), J_(ab)=15.7Hz, 1H), 4.62 (s, 1H), 4.29-4.18 (m, 4H), 4.09-4.00 (m, 2H), 3.91-3.71(m, 2H), 3.16-2.78 (m, 4H), 2.55-2.50 (m, 4H), 2.43 (s, 1.5H), 2.41 (s,1.5H), 2.23 (m, 1H), 2.21 (s, 1.5H), 2.16 (s, 1.5H), 1.84 (brs, 2H).

Example 7

1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2-morpholin-4-yl-ethyl)-1,3-dihydro-benzoimidazol-2-one

A solution of1-(1-{3-[5-acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one(130 mg, 0.22 mmol) in DMF (1 mL) was treated with cesium carbonate (146mg, 0.45 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (329 mg,2.2 mmol) at 25° C. and stirred for 24 h before it was diluted withEtOAc (10 mL) and H₂O (5 mL). The organic layer was separated, washedwith H₂O (2×5 mL), dried over Na₂SO₄, and concentrated. Columnchromatography (silica, 5% MeOH/CH₂Cl₂) afforded 124 mg (81%) of a whitepowder. TLC (10% MeOH/CH₂Cl₂): R^(f)=0.31. MS (electrospray): m/z 696.3([M+H]⁺, C₃₆H₄₄F₃N₇O₄ requires 695.3). ¹H NMR (CDCl₃, 400 MHz, a mixtureof two rotamers): 7.82 and 7.65 (AB pattern, J_(ab)=8.2 Hz, 2H), 7.74and 7.68 (AB pattern, J_(ab)=8.4 Hz, 2H), 7.23-7.05 (m, 4H), 4.92 and4.80 (AB pattern, J_(ab)=15.6 Hz, 1.2H), 4.69 (s, 0.8H), 4.38-4.00 (m,5H), 4.02 (t, J=7.0 Hz, 2H), 3.92-3.70 (m, 2H), 3.70 (t, J=4.5 Hz, 4H),3.15-2.80 (m, 4H), 2.70 (t, J=7.1 Hz, 2H), 2.60-2.20 (m, 9H), 2.24 (s,1.6H), 2.18 (s, 1.4H), 1.85-1.75 (m, 2H).

Example 8

1-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihydro-benzoimidazol-2-oneA.3-(4-Bromo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester

To a stirred solution of 500.0 g (2.51 mol) of1-tert-butoxycarbonyl-4-piperidone and 87.1 g (2.76 mol) of morpholinein benzene (1.25 L) was added a catalytic amount (˜0.25 g) of p-TsOH.The mixture was heated to reflux for 36 h with a Dean-Stark trap. Thesolvent was removed under reduced pressure to give a brown oil, whichsolidified on standing. The crude product was divided and 335.0 g (1.25mol) of the enamine was diluted with CH₂Cl₂ (1.25 L) and 175.0 mL (1.25mol) of Et₃N was added. The mixture was cooled to 0° C. and a solutionof 275.0 g (1.25 mol) of 4-bromobenzoyl chloride in CH₂Cl₂ (150 mL) wasadded slowly by dropping funnel over 1 h. The mixture was allowed towarm to rt and stir overnight. The reaction was then diluted with 1 NHCl (450 mL) and stirred vigorously for 3 h. The aqueous layer wasextracted with CH₂Cl₂ (3×500 mL) and the combined extracts were driedover Na₂SO₄ and the solvent was removed under reduced pressure. Thecrude oil was diluted with EtOH (850 mL) and cooled to 0° C. To thisstirred solution was slowly added 120.0 g (3.75 mol) of hydrazine andthe mixture was allowed to warm to rt and stir overnight during whichtime a white precipitate formed. The volume of the reaction was reducedto ˜350 mL and EtOAc (1.50 L) was added to the mixture. The suspensionwas stirred vigorously for 2 h and was filtered then washed with EtOAc(2×500 mL) and dried under vacuum to afford 309.0 g (62% over 3 steps)of a white solid. TLC (silica, 5% MeOH/CH₂Cl₂): R_(f)=0.3. MS(electrospray): m/z calculated for C₁₇H₂₀BrN₃O₂ [M⁺+H] 378.07, observed378.0. ¹H NMR (400 MHz, CDCl₃): 7.65-7.26 (m, 4H), 4.64 (br s, 2H),3.84-3.68 (br m, 2H), 2.87-2.74 (br m, 2H), 1.48 (br s, 9H).

B. 3-(4-Bromophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridiniumtrifluoroacetate

To a stirred solution of 10.0 g (26.4 mmol) of the3-(4-bromo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester in CH₂Cl₂ (26.0 mL) was added 26.0 mL of TFA. Theresulting mixture was allowed to stir overnight. The solvent was removedunder reduced pressure and the solid was dried in vacuo. The dried solidwas suspended in Et₂O and stirred vigorously for 2 h and then filteredand dried in vacuo to give 10.1 g of a white solid, which was usedwithout further purification. TLC (silica, 10% MeOH/CH₂Cl₂): R_(f)=0.05.MS (electrospray): m/z calculated for C₁₂H₁₂BrN₃ [M⁺+H] 278.02, observed278.0.

C.3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

To a stirred solution of 3.11 g (11.1 mmol) of3-(4-bromophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridiniumtrifluoroacetate and 4.71 mL (33.5 mmol) of Et₃N in DMF (55 mL) wasslowly added 1.21 mL (15.6 mmol) of methanesulfonyl chloride. After 2.5h, the solvent was removed under reduced pressure and the residue wasdiluted with CH₂Cl₂ (100 mL) and saturated NaHCO₃ (100 mL). The layerswere separated and the aqueous phase was extracted with CH₂Cl₂ (2×30mL). The combined organic layers were dried over Na₂SO₄ and the solventwas removed under reduced pressure. Purification by columnchromatography (silica, 0-5% MeOH/CH₂Cl₂) afforded 2.01 g (50%) of thetitle compound. TLC (silica, 5% MeOH/CH₂Cl₂): R_(f)=0.3. MS(electrospray): m/z calculated for C₁₃H₁₄BrN₃O₂S [M⁺+H] 356.00, observed356.0.

D.3-(4-Bromo-phenyl)-5-methanesulfonyl-1-oxiranylmethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

To a stirred solution of 2.50 g (7.00 mmol) of3-(4-bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridineand 5.52 mL (70.0 mmol) of epichlorohydrin was added 2.50 g (7.72 mmol)of solid Cs₂CO₃. The reaction was allowed to stir for 48 h and thesolvent was removed under reduced pressure. The residue was then dilutedwith H₂O (150 mL) and EtOAc (150 mL). The layers were separated, and theorganic layer was washed with H₂O (50 mL) and brine (50 mL), dried overNa₂SO₄ and the solvent was removed under reduce pressure. Purificationby flash chromatography (silica, 0-20% acetone/CH₂Cl₂) afforded 1.52 g(53%) of a white solid. TLC (silica, 5% MeOH/CH₂Cl₂): R_(f)=0.5. MS(electrospray): mlz calculated for C₁₆H₁₈BrN₃O₃S [M⁺+H] 412.03, observed412.0. ¹H NMR (400 MHz, CDCl₃): 7.54 and 7.47 (A and B of AA′BB′, J=8.6Hz, 4H), 4.56-4.45 (m, 3H), 4.10 (dd, J=15.1, 5.4 Hz, 1H), 3.73-3.58 (m,2H), 3.38-3.32 (m, 1H), 2.96-2.87 (m, 2H), 2.86 (s, 3H), 2.83 (dd,J=4.4, 4.2 Hz, 1H), 2.48 (dd, J=4.6, 2.6 Hz, 1H).

E.1-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4.3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihydro-benzoimidazol-2-one

A stirred solution of 25.0 mg (0.061 mmol) of3-(4-bromo-phenyl)-5-methanesulfonyl-1-oxiranylmethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridineand 19.0 mg (0.073 mmol) of6-chloro-1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one in EtOH (0.5mL) was heated to 80° C. in a sealed vessel for 16 h. The reaction wascooled and the solvent was removed under reduced pressure. The crudeproduct was purified by column chromatography (silica, 0-5% MeOH/CH₂Cl₂)to afford 0.025 g (63%) of the title compound. TLC (silica, 5%MeOH/CH₂Cl₂): R_(f)=0.4. MS (electrospray): m/z calculated forC₂₈H₃₂BrClN₆O₄S [M⁺+H] 663.11, observed 663.0. ¹H NMR (400 MHz, CDCl₃):10.2 (s, 1H), 7.52 and 7.46 (A and B of AA′BB′, J=8.6 Hz, 4H), 7.15 (brd, J=1.5 Hz, 1H), 7.04-6.95 (m, 2H), 4.52 and 4.49 (A and B of ABquartet, J_(ab)=14.5 Hz, 2H), 4.33-4.14 (m, 3H), 4.07-3.97 (m, 1H),3.74-3.58 (m, 2H), 3.17-2.89 (m, 4H), 2.86 (s, 3H), 2.57-2.30 (m, 5H),2.20 (t, J=11.1 Hz,1H), 1.87-1.73 (m, 2H).

Example 9

[3-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-acetonitrileA.3-(4-Trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester

To a stirred solution of 500 g (2.51 mol) of1-tert-butoxycarbonyl-4-piperidone and 87.1 g (2.76 mol) of morpholinein benzene (1.25 L) was added a catalytic amount (˜0.25 g) of p-TsOH.The mixture was heated to reflux for 36 h with a Dean-Stark trap. Onehalf of the solvent was removed under reduced pressure and the resultingsolution was cooled and filtered. The filtrate was then concentrated toyield 630 g (94%) of an orange red oil. The eneamine was divided and 320g (1.19 mol) was diluted with CH₂Cl₂ (1.0 L) and 165.0 mL (1.19 mol) ofEt₃N was added. The mixture was cooled to 0° C. and a solution of 225 g(1.08 mol) of 4-trifluoromethylbenzoyl chloride in CH₂Cl₂ (0.5 L) wasadded slowly by dropping funnel over 1 h. The mixture was allowed towarm to rt and stir overnight. The reaction was then diluted with 1 NHCl (450 mL) and stirred vigorously for 3 h. The aqueous layer wasextracted with CH₂Cl₂ (3×500 mL) and the combined extracts were driedover Na₂SO₄ and the solvent was removed under reduced pressure. Thecrude oil was diluted with EtOH (1 L) and cooled to 0° C. To thisstirred solution was slowly added 115 g (3.57 mol) of hydrazine and themixture was allowed to warm to rt and stir overnight during which time awhite precipitate formed. The volume of the reaction was reduced to ˜500mL and cooled. The precipitate was collected to afford 285 g (72% fromeneamine) of a white solid. ¹H NMR (400 MHz, CDCl₃): 7.63-7.55 (m, 4H),4.58 (br s, 2H), 3.69-3.62 (br m, 2H), 2.74-2.68 (br m, 2H), 1.47 (s,9H).

B.1-(2-Methoxycarbonyl-ethyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester

3-(4-Trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester (1.85 g, 5.04 mmol) and methyl acrylate (0.50 mL,5.6 mmol) were combined in toluene (30 mL) and heated to 75° C. Theresulting mixture was treated with t-BuONa (100 mg), and heatingcontinued for 48 h. The mixture was allowed to cool and partitionedbetween EtOAc (300 mL) and NaHCO₃ (75 mL). The aqueous layer wasextracted with EtOAc (3×75 mL). The combined extracts were dried overNa₂SO₄ and concentrated. Column chromatography (silica, 30-60%EtOAc/hexanes) afforded 343 mg (15%) of the title compound. TLC (silica,50% EtOAc/hexanes): R_(f)=0.4. MS (electrospray): m/zcalculated forC₂₂H₂₇F₃N₃O₄ [M⁺+H] 454.20, found 454.1. ¹H NMR (CDCl₃, 400 MHz): 7.75(br d, J=8.1 Hz, 2H), 7.64 (br s, 2H), 4.63 (br s, 2H), 4.30 (t, J=6.6Hz, 2H), 3.75 (br s, 2H), 3.68 (s, 3H), 2.98 (t, J=6.6 Hz, 2H), 2.79 (brt, J=5.6 Hz, 2H), 1.48 (s, 9H).

C.1-(3-Hydroxy-propyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester

A solution of LiBH₄ (26 mg, 1.2 mmol) in THF (0.5 mL) was added to a 0°C. solution of1-(2-methoxycarbonyl-ethyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester (317 mg, 0.70 mmol) in THF (4.0 mL). The mixturewas stirred for 5 min then additional LiBH₄ (15 mg) was added andstirring continued for 17 h. The mixture was partitioned between EtOAc(80 mL) and saturated aqueous NaHCO₃ (20 mL). The aqueous layer wasextracted with EtOAc (2×20 mL). The combined extracts were dried overNa₂SO₄ and concentrated. Column chromatography (silica, 0-8%MeOH/CH₂Cl₂) afforded 268 mg (95%) of the title compound. HPLC (reversephase conditions), t_(R)=6.82 min. MS (electrospray): m/z calculated forC₂₁H₂₆F₃N₃O₃ [M⁺+Na] 448.18, found 448.10. ¹H NMR (CDCl₃, 400 MHz): 7.73(br d, J=8.2 Hz, 2H), 7.65 (br s, 2H), 4.64 (br s, 2H), 4.21 (t, J=6.4Hz, 2H), 3.76 (br s, 2H), 3.66 (t, J=5.7 Hz, 2H), 2.73 (br t, J =5.4 Hz2H), 2.04 (q, J=6.1, 2H), 1.48 (s, 9H).

D. 4-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acidtert-butyl ester

1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (7.24 g, 34.1 mmol) anddi-tert-butyl dicarbonate (9.12 g, 41.0 mmol) were combined in DMF (80mL) and the mixture heated to 40° C. under N₂ for 17 h. The mixture wasallowed to cool, diluted with EtOAc (800 mL) and washed with saturatedaq. NaHCO₃ (150 mL), H₂O (3×150 mL) and brine (150 mL). The combinedaqueous washes were extracted with EtOAc (2×150 mL). The combinedextracts were dried over Na₂SO₄ and concentrated to afford 12.4 g of thetitle compound. TLC (silica, 50% EtOAc/hexanes): R_(f)=0.3. MS(electrospray): m/zcalculated for C₁₇H₂₃N₃O₃ [M⁺+Na] 340.16, found340.1. ¹H NMR (CDCl₃, 400 MHz): 10.59 (s, 1 H), 7.15-7.11 (m, 2H),7.08-7.02 (m, 2H), 4.49 (tt, J=8.4, 4.0 Hz, 1 H), 4.32 (br s, 2H), 2.89(br t, J=11.6, 2H), 2.34 (dq, J=12.6, 4.4 Hz, 2H), 1.83 (br d, J=10.5Hz, 2H) 1.36 (s, 9H).

E. (2-Oxo-3-piperidin-4-yl-2,3-dihydro-benzoimidazol-1-yl)-acetonitrile

A solution of4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acidtert-butyl ester (2.91 g, 9.16 mmol) in THF (10 mL) was added dropwiseto a solution of KHMDS (2.19 g, 11.0 mmol) in THF (20 mL). The mixturewas stirred for 10 min then bromoacetonitrile (3.2 mL, 46 mmol) wasadded. The resulting mixture was stirred for 4 h then partitionedbetween EtOAc (750 mL) and saturated aqueous NaHCO₃ (200 mL). The EtOAclayer was washed with H₂O (3×200 mL) and brine (200 mL). The combinedwashes were extracted with EtOAc (2×150 mL). The combined extracts weredried over Na₂SO₄ and concentrated. Column chromatography (silica,20-60% EtOAc/hexanes) afforded 2.20 g (67%) of4-(3-cyanomethyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylicacid tert-butyl ester. The purified material was dissolved in CH₂Cl₂ (40mL) and diluted with TFA (25 mL). The resulting mixture was stirred for1 h then diluted with CH₂Cl₂ (250 mL) and washed with 1 N NaOH (100 mL).The aqueous layer was extracted with CH₂Cl₂ (2×100 mL). The combinedextracts were dried over Na₂SO₄ and concentrated to 1.59 g (95%) of thetitle compound which was suitable for further use without purification.TLC (silica, 5% MeOH/CH₂Cl₂): R_(f)=0.1. MS (electrospray): m/zcalculated for C₁₄H₁₇N₄O [M⁺+H] 257.14, found 257.1. ¹H NMR (CDCl₃, 400Hz): 733-7.29 (m, 1H), 7.17-7.02 (m, 3H), 4.75 (s, 2H), 4.41 (tt,J=12.2, 4.4 Hz, 1 H), 3.28 (br d, J=9.8 Hz, 2H), 3.11 (br s, 1 H), 2.80(t, J=10.0 Hz, 2H), 2.37 (dq, J=12.5, 4.2 Hz, 2H), 1.83 (br d, J=11.8Hz, 2H).

F.[3-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-acetonitrile

1-(3-Hydroxy-propyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester (268 mg, 0.63 mmol) was dissolved in CH₂Cl₂ (10mL) and TFA (10 mL). The mixture was stirred for 1 h then concentratedto dryness. The residue was dissolved in CH₂Cl₂ (4.0 mL), cooled to 0°C. and treated with i-Pr₂NEt (0.36 mL, 2.1 mmol), followed bymethanesulfonyl chloride (0.16 mL, 2.1 mmol). The reaction mixture wasstirred for 4 h, then diluted with EtOAc (200 mL) and washed withsaturated aqueous NaHCO₃ (2×25 mL). The washes were extracted with EtOAc(2×25 mL). The combined extracts were dried over Na₂SO₄ andconcentrated. A portion of the crude mesylate (197 mg, ca. 0.41 mmol)was combined with(2-oxo-3-piperidin-4-yl-2,3-dihydro-benzoimidazol-1-yl)-acetonitrile(321 mg, 1.25 mmol) in CH₂Cl₂ (2.0 mL) and DMF (0.5 mL). The resultingmixture was treated with i-Pr₂NEt (0.22 mL, 1.3 mmol) and stirred for 60h. The reaction mixture was partitioned between EtOAc (150 mL) andsaturated aqueous NaHCO₃ (75 mL). The EtOAc layer was washed with H₂O(2×75 mL), and brine (75 mL). The combined washes were extracted withEtOAc (3×50 mL). The combined extracts were dried over Na₂SO₄ andconcentrated. Purification of the residue by preparative TLC (silica, 1%MeOH/CH₂Cl₂ then 25% acetone/CH₂Cl₂) gave 37 mg (14%) of the titlecompound. HPLC (reverse phase conditions), t_(R)=2.94 min. MS(electrospray): m/z calculated for C₃₁H₃₅F₃N₇O₃S [M⁺+H] 642.25, found642.25. ¹H NMR (CDCl₃, 400 MHz): 7.73 and 7.76 (A and B of AA′BB′J_(ab)=8.2 Hz, 4H), 7.26-7.05 (m, 4H), 4.81 (s, 2H), 4.56 (s, 2H), 4.26(m, 1H), 4.15 (t, J=6.8 Hz, 2H), 3.70 (t, J=5.8 Hz, 2 H), 3.03 (br d,J=11.1 Hz, 2H), 2.95 (t, J=5.7 Hz, 2H), 2.91 (s, 3H), 2.43 (m, 4), 2.12(m, 4H), 1.82 (br d, J=9.9 Hz, 2H).

Example 10

5-Chloro-3-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-dihydro-benzoimidazol-2-oneA. 1-Methanesulfonyl-piperidin-4-one

Potassium carbonate (324 g, 2340 mmol) was added to a solution of4-piperidone monohydrate hydrochloride (90 g, 586 mmol) in chloroform(300 mL) and water (300 mL). The slurry was cooled to 0° C. and treatedwith methylsulfonyl chloride (136 mL, 1760 mmol) by dropwise additionover a 1 h period. The reaction mixture was allowed to shake for 72 hand was partitioned between CH₂Cl₂ (500 mL) and saturated aqueous NaHCO₃(500 mL). The aqueous layer was extracted with CH₂Cl₂ (3×200 mL). Theorganic layer was washed with 1% KHSO₄ (250 mL), dried (Na₂SO₄), andconcentrated to afford 90.5 g (87%) of a white solid. HPLC (reversephase conditions), t_(R)=2.19 min. MS (electrospray): exact masscalculated for C₆H₁₁NO₃S, 177.1; m/z found, 178.1 [M+H]⁺. 1H NMR (400MHz, CDCl₃): 3.60 (t, J=6.5 Hz, 4H), 2.89 (s, 3H), 2.59 (t, J=6.3 Hz,4H).

B.5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

p-Toluenesulfonic acid (1.34 g, 7.0 mmol) and morpholine (25.83 mL, 296mmol) were added to a solution of 1-methanesulfonyl-piperidin-4-one(50.0 g. 282 mmol) in benzene (282 mL). The reaction mixture was heatedin a flask equipped with a condenser and a Dean-Stark trap at reflux for15 h. The reaction mixture was cooled and concentrated in vacuo to givethe enamine which was used without further purification. The enamine wasdissolved in CH₂Cl₂ (200 mL) and cooled to 0° C. To this was addedtriethylamine (47.2 mL, 339 mmol) followed by dropwise addition of4-trifluoromethylbenzoyl chloride (42.3 mL, 285 mmol) dissolved inCH₂Cl₂ (82 mL). The reaction mixture was allowed to warm to roomtemperature and stirred for 20 h. The reaction mixture was washed with 1N HCl (250 mL) and the CH₂Cl₂ layer was separated, dried (Na₂SO₄), andconcentrated. The resulting oil was taken up in ethanol (300 mL) andtreated with hydrazine (44.3 mL, 1.41 mol) at 0° C. The reaction mixturewas allowed to warm to room temperature and stirred for 24 h. Themixture was concentrated and the resulting solid was filtered withethanol wash and dried in vacuo to afford 70 g (72%) of5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridineas a white solid. HPLC (reverse phase conditions), t_(R)=6.33 min. MS(electrospray): exact mass calculated for C₁₄H₁₄F₃N₃O₂S, 345.0; m/zfound, 346.0 [M+H]⁺. 1H NMR (400 MHz, CDCl₃): 7.72 (s, 4H), 4.58 (s,2H), 3.69 (t, J=5.7 Hz, 2H), 2.99 (t, J=5.7 Hz, 2H), 2.92 (s, 3H).

C.3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-1-ol

Cs₂CO₃ (33.74 g, 103.5 mmol) was added to a solution of5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(29.8 g, 86.3 mmol) in anhydrous DMF (70 mL) and stirred for 25 min.3-Bromo-1-propanol (8.6 mL, 13.2 g, 94.9 mmol) was added and stirredunder N₂ at room temperature for 18 h. Water (500 mL) was added to thereaction and stirred for 5 min. The precipitated material was filteredout and washed with water (4×100 mL) and dried in a Freeze DryingSystem. The crude material (31.0 g) was taken up in anhydrous DMF (65mL) and Cs₂CO₃ (33.74 g, 103.5 mmol) was added, and stirred for 10 min.3-Bromo-1-propanol (8.6 mL, 13.2 g, 94.9 mmol) and MeOH (6.0 mL, 4.75 g,148 mmol) were added and stirring continued under N₂ at rt for 15 h.Water (500 mL) was added to the reaction and stirred for 10 min. Theprecipitated material was filtered and washed with water (3×100 mL). Thefilter cake was dissolved in CH₂Cl₂ (200 mL) and washed with brine (50mL), dried (Na₂SO₄), and concentrated. The solid was triturated withEt₂O (200 mL), filtered, then washed with Et₂O, and dried to furnish16.0 g of the desired compound. The mother liquor was chromatographed(silica, 0-10% acetone/EtOAc) to obtain an additional 3.0 g of the titlecompound. The combined yield was 54.6%. MS (electrospray): exact masscalculated for C₁₇H₂₀F₃N₃O₃S, 403.12; m/z found, 404.0 [M+H]⁺, 426.0[M+Na]⁺. 1H NMR (400 MHz, CDCl₃): 7.71 (d, J=8.2 Hz, 2H), 7.66 (d, J=8.5Hz, 2H), 4.55 (s, 2H), 4.23 (t, J=6.5 Hz, 2H), 3.70-3.63 (m, 4H), 2.90(s, 3H), 2.90 (t, J=5.1 Hz, 2H), 2.62 (t, J=5.9 Hz, 1H), 2.06 (q, J=6.1Hz, 2H).

D. 5-Chloro-1-methyl-3-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one

To a stirred suspension of 0.97 g (2.99 mmol) of4-(6-chloro-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylicacid ethyl ester in THF (30 mL) was added 0.5 M KHMDS in toluene. Thismixture was stirred for 1 h and 0.25 mL (3.89 mmol) of Mel was added inone portion. After 1.5 h the reaction was diluted with 1 N HCl (75 mL)and EtOAc (75 mL). The layers were separated, and the organic layer waswashed with H₂O (50 mL) and brine (50 mL), dried over Na₂SO₄ and thesolvent was removed under reduced pressure. Purification by flashchromatography (silica, 0-5% MeOH/CH₂Cl₂) afforded 0.92 g (91%) of awhite solid. A suspension of 0.92 g (2.72 mmol) of the ethyl carbamatein 1:1 EtOH (7.0 mL) and 10% NaOH (7.0 mL) was heated to 110° C. for 36h and then cooled. The mixture was diluted with EtOAc (30 mL) and H₂O.The layers were separated and the aqueous phase was extracted with EtOAc(2×30 mL). The combined organic layers were dried over Na₂SO₄ and thesolvent was removed under reduced pressure to afford 0.56 g (78%) of apale yellow solid. TLC (silica, 10% MeOH/CH₂Cl₂): R_(f)=0.1. MS(electrospray): m/z calculated for C₁₃H₁₆ClN₃O [M⁺+H] 266.10, observed266.0. ¹H NMR (400 MHz, CDCl₃): 7.28 (d, J=1.8 Hz, 2H), 7.05 (dd, J=8.3,2.0 Hz, 1H), 6.87 (d, J=8.3 Hz, 1H), 4.41 (tt, J=12.5, 4.3 Hz, 1H), 3.39(s, 3H), 3.30 (br d, J=11.9 Hz, 2H), 2.82 (dt, J=12.4, 2.0 Hz, 2H ),2.30 (dq, J=12.3, 4.3 Hz, 2H), 1.81 (br dd, J=12.1, 2.3 Hz, 2H).

E.5-Chloro-3-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-dihydro-benzoimidazol-2-one

To a stirred solution of 0.33 mL (3.72 mmol) of oxalyl chloride inCH₂Cl₂ (10 mL) under N₂ at −78° C. was added 0.36 mL (4.96 mmol) of DMSOand the reaction was stirred for 15 min. To this solution was added asolution of 1.0 g (2.48 mmol) of3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-1-olin 10 mL over 10 min and stirring was continued for 25 min. To thissolution was added 1.40 mL (9.92 mmol) of Et₃N and the reaction wasstirred for 10 min at −78° C. and was then allowed to warm to rt andstir for 1 h. The mixture was diluted with EtOAc (75 mL) and saturatedNaHCO₃ (75 mL) and the layers were separated. The combined organiclayers were dried over Na₂SO₄ and the solvent was removed under reducedpressure. The resulting solid was dried in vacuo and was suspended inEt₂O (20 mL) and stirred vigorously for 1 h. The solid was filtered andwashed with Et₂O (2×10 mL) to afford the crude aldehyde which wascarried on without further purification. The crude aldehyde,5-chloro-1-methyl-3-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (0.60g, 2.3 mmol), and 0.20 mL (3.72 mmol) of AcOH was dissolved in CH₂Cl₂(15 mL) followed by 0.69 g (3.25 mmol) of NaBH(OAc)₃, and the reactionwas allowed to stir overnight. The mixture was diluted with CH₂Cl₂ (75mL) and saturated NaHCO₃ (75 mL) and the layers were separated. Thecombined organic layers were dried over Na₂SO₄ and the solvent wasremoved under reduced pressure. Purification by flash chromatography(silica, 0-4% MeOH/CH₂Cl₂) afforded 1.28 g (79% over 2 steps) of a whitesolid. TLC (silica, 5% MeOH/CH₂Cl₂): R_(f)=0.5. MS (electrospray): m/zcalculated for C₃₀H₃₄ClF₃N₆O₃S [M⁺+H] 651.21, observed 651.2. ¹H NMR(400 MHz, CDCl₃): 7.71 and 7.63 (A and B of AA′BB″, J_(AB)=8.17 Hz, 4H),7.16 (d, J=1.8 Hz, 1H), 7.04 (d, J=8.3, 1.8 Hz, 1H), 6.86 (d, J=8.3Hz,1H), 4.55 (s, 2H), 4.23 (tt, J=12.4, 4.3Hz, 1H), 4.13 (t, J=6.7 Hz, 2H),3.69 (t, J=5.7 Hz, 2H), 3.36 (s, 3H), 3.0 (d, J=11.6 Hz 2H), 2.95 (t,J=5.7 Hz, 2H), 2.90 (s, 3H), 2.45-2.32 (m, 4H), 2.16-2.04 (m, 4H), 1.76(dd, J=11.9, 2.0 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃): 171.0, 153.7, 144.7,137.1, 136.8, 129.3, 129.0, 128.7, 126.4, 125.5 (q, J=3.8 Hz), 122.7,120.7, 109.8, 109.2, 108.0, 60.3, 54.7, 53.0, 51.3, 46.8, 43.1, 42.4,36.8, 29.0, 27.2, 27.0, 22.3, 21.0, 14.1.

Example 11

1-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-oneA. Methyl 2-nitrophenylacetate

2-Nitrophenylacetic acid (60 g, 0.3 mol) was set stirring in 250 mL ofmethanol. Sulfuric acid (0.5 mL) was added and the mixture heated toreflux. After 20 h the mixture was cooled and evaporated under reducedpressure to give a clear yellow oil. The oil was brought up in EtOAc andwashed with saturated NaHCO₃. The organics were dried (MgSO₄) andevaporated to give 63 g (98%) of the ester as a clear orange liquid. TLC(silica, 25% EtOAc/hexanes): R_(f)=0.36. ¹H NMR (400 MHz, CDCl₃): 8.24(m, 1H), 7.16 (m, 1H), 7.60 (m, 1H), 7.47 (m, 1H), 4.15 (s, 2H), 3.83(s, 3H).

B. Methyl 2-aminophenylacetate

Methyl 2-nitrophenylacetate (10.1 g, 51.2 mmol) in 125 mL of methanolcontaining 221 mg of 10% Pd/C was placed on the Parr hydrogenator at 40psi. After 5 h the mixture was filtered through celite and evaporatedunder reduced pressure to give a clear red oil. The solvent wasevaporated under reduced pressure to give 8.5 g (100%) of methyl2-aminophenylacetate as a clear red oil. TLC (silica, EtOAc/hexanes):R_(f)=0.24. ¹H NMR (400 MHz, CDCl₃): 7.21 (m, 2H), 6.86 (m, 2H), 3.81(s, 3H), 3.70 (s, 2H).

C. 4-(2-Oxo-2,3-dihydro-indol-1-yl)-piperidine-1-carboxylic acidtert-butyl ester

Methyl 2-aminophenylacetate (3.0 g, 18.2 mmol) and1-tert-butoxycarbonyl-4-piperidone (4.5 g, 22.6 mmol) were set stirringin 50 mL of CH₂Cl₂ under an atmosphere of nitrogen. Sodiumtriacetoxyborohydride (5.4 g, 25.5 mmol) was added followed by 1 mL ofacetic acid. After 20 h at rt the mixture was quenched by the slowaddition of saturated NaHCO₃. After stirring for 30 min, the organicswere separated, dried (MgSO₄), and evaporated to afford 7.5 g of apurple oil. Purification by column chromatography (silica, 10-50%EtOAc/hexanes) gave 3.9 g (62%) of the title compound. TLC (silica, 25%EtOAc/hexanes): R_(f)=0.15. ¹H NMR (400 MHz, CDCl₃): 7.25 (m, 2H), 7.01(m, 2H), 4.40 (m, 1 H), 3.53 (s, 2H), 2.83 (m, 2H), 2.32 (m, 2H), 1.70(m, 2H), 1.51 (s, 9H).

D. 1-Piperidin-4-yl-1,3-dihydro-indol-2-one

4-(2-Oxo-2,3-dihydro-indol-1-yl)-piperidine-1-carboxylic acid tert-butylester (3.9 g, 12.3 mmol) was set stirring in 30 mL of 1:1 TFA/CH₂Cl₂.After 45 min the solvent was evaporated under reduced pressure to give aclear purple oil. The oil was brought up in diethyl ether and cooled onice to give a precipitate. The solid was filtered, washed with ether andair dried to give 4.0 g (100%) of the title compound as a TFA salt. ¹HNMR (400 MHz, DMSO-d₆): 8.6 (br s, 1H), 7.27 (m, 3H), 7.03 (m, 1 H),4.45 (m, 1H), 3.56 (s, 2H), 3.42 (m, 2H), 3.09 (m, 2H), 2.53 (m, 2H),1.78 (m, 2H).

E.1-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-one

3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-1-ol(304 mg, 0.754 mmol) was set stirring in 5 mL of CH₂Cl₂ at rt undernitrogen. Dess-Martin reagent (394 mg, 0.929 mmol) was added in oneportion and the reaction mixture was left stirring. After 1.5 h themixture was added to a stirring solution of thiosulphate (10 equiv) in20 mL of water and 5 mL of saturated NaHCO₃. After 2 h the organic layerwas separated, dried (MgSO₄) and evaporated to give the aldehyde as alight yellow solid. The above aldehyde (303 mg, 0.754 mmol) and1-piperidin-4-yl-1,3-dihydro-indol-2-one were set stirring in 15 mL ofCH₂Cl₂ containing Et₃N (0.15 mL, 1.1 mmol). A solution of Na(AcO)₃BH in5 mL of CH₂Cl₂ was added dropwise via pipette over 10 min and themixture was left to stir overnight. The mixture was quenched withsaturated NaHCO₃ and the organic layer separated. The organics weredried (MgSO₄) and evaporated to a clear purple oil. Purification withcolumn chromatography (silica, 50-100% acetone/CH₂Cl₂) gave 240 mg (53%)of a light pink solid. TLC (silica, 50% acetone/CH₂Cl₂): R_(f)=0.17. ¹HNMR (400 MHz, DMSO-d₆): 7.82 (m, 4H), 7.24 (m, 2H), 7.11 (m, 1H), 6.98(m, 1H), 4.49 (s, 2H), 4.12 (m, 3H), 3.54 (s, 2H 3.32 (s, 4H), 2.95 (m,7H), 2.32 (m, 4H), 1.99 (m, 4H), 1.55 (m, 2H).

Example 12

1-[3-(4-Chloro-3-methyl-phenyl)-1-(3-{4-[3-(4-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-2-hydroxy-propyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

1-[3-(4-Chloro-3-methyl-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone(0.069 g. 0.20 mmol) was dissolved in CH₂Cl₂ (1 mL), and4-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]piperidine (0.105 g, 0.4mmol) was added, followed by Yb(OTf)₃ (0.031 g, 0.22 mmol). The mixturewas stirred at room temperature for 16 h. Preparative TLC (silica, 7.5%MeOH/CH₂Cl₂) afforded 84 mg (69%) of the title compound. MS(electrospray): exact mass calculated for C₃₁H₃₄Cl₂N₆O₃, 608.21; m/zfound, 609.2 [M⁺+H]. ¹H NMR (400 MHz, CDCl₃, 1:1 mixture of rotamers):8.00 (d, J=8.4 Hz, 2H), 7.56-7.53 (m, 1H), 7.48-7.42 (d, J=8.6 Hz, 2H),7.41-7.30 (m, 2H), 4.84 and 4.73 (A and B of AB quartet J=15.6Hz, 1H),4.62 (br s, 1H), 4.25-4.13 (m, 2H), 4.10-3.98 (m, 2H), 3.90-3.70 (m,2H), 3.04-2.71 (m, 5H), 2.51-2.40 (m, 6H), 2.30-2.15 (m, 6H), 2.10-1.90(m, 2H).

Example 13

1-[1-{2-Hydroxy-3-[4-(5-trifluoromethyl-benzothiazol-2-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone.

A. 2-Piperidin-4-yl-5-trifluoromethyl-benzothiazole

To a stirred solution of 5 g (29.2 mmol) of1-acetyl-piperidine-4-carboylic acid in toluene (100 mL) and a catalyticamount of DMF (1 mL) was added dropwise 2.4 mL of oxalyl chloride (33.3mmol). The reaction mixture was allowed to stir at room temperatureovernight. A 20 mL aliquot (6 mmol) of the acid chloride solution wasthen placed in a separate flask and treated with a solution of 1.4 g(6.10 mmol) of 2-amino-4-(trifluoromethyl)thiophene hydrochloride intriethyl amine (4 mL). The reaction was then heated to 80° C. for 30 minand then partitioned between ethyl acetate (50 mL) and water (20 mL) andseparated. The aqueous layer was further extracted with EtOAc (2×30 mL).The combined organic layers were then washed with water (25 mL), brine,dried over Na₂SO₄, and the solvent was removed under reduced pressure.This was then heated to 60° C. in a 1 N HCl/MeOH solution overnight withstirring. The reaction mixture was cooled and concentrated to dryness.The solid was then taken back up in 35 mL MeOH and stirred over sodiumbicarbonate (1 g) for 1 h then filtered and stripped to give 1.05 g(60%) of the desired product which was used without furtherpurification. MS (electrospray): exact mass calculated for C₁₃H₁₃F₃N₂S,286.08; m/z found, 287.1 [M⁺H]+. ¹H NMR (CDCl₃, 400 MHz): 8.25 (s, 1H),7.98 (d, J=8.41 Hz, 1H), 7.65 (d, J=8.41 Hz, 1H), 3.38 (tt, J=11.35,4.11 Hz, 1H), 3.28 (ddd, J=13.69, 11.74, 2.74 Hz, 1H), 3.16 (ddd,J=13.89, 11.15, 2.74 Hz, 1H), 2.85 (m, 1H), 2.25 (br m, 2H), 1.97 (br m,2H).

B.1-[1-{2-Hydroxy-3-[4-(5-trifluoromethyl-benzothiazol-2-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

A solution of 63 mg (0.22 mmol)2-piperidin-4-yl-5-trifluoromethyl-benzothiazole was dissolved in 4 mLEtOH and treated with 40 mg (0.11 mmol) of1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone.The solution was heated to 60° C. overnight. The solvent was thenremoved by rotary evaporation and the crude product was purified bycolumn chromatography (silica, 0-10% MeOH/EtOAc) to afford 57 mg (80%)of a white solid. MS (electrospray): exact mass calculated forC₃₁H₃₁F₆N₅O₂S, 651.21; m/z found, 652.2 [M+H]⁺. ¹H NMR (CDCl₃, 400 MHz,a mixture of amide rotamers): 8.24 (s, 1H), 7.97 (d, J=8.41 Hz, 1H),7.78 (d, J=8.41 Hz, 1H), 7.70 (m, 2H), 7.65 (d, J=8.41 Hz, 1H), 7.60(dd, J=8.41, 1.37 Hz, 1H), 4.88 and 4.76 (A and B of AB quartet, J=15.85Hz, 1H), 4.66 (br s, 1H), 4.25-4.15 (m, 2H), 4.08-3.99 (m, 1.5H),3.91-3.83 (m, 0.5H), 3.82-3.68 (m, 1H), 3.16 (tt, J=11.35, 3.52 Hz, 1H),3.12-3.06 (m, 1H), 3.02-2.97 (m, 1H), 2.9-2.87 (m, 1.4H), 2.87-2.75 (m,0.6H), 2.55-2.43 (m, 3H), 2.27-2.17 (m, 3H), 2.21 (s, 1.5H), 2.17 (s,1.5H), 2.04-1.87 (m, 2H).

Example 14

1-[1-{3-[4-(Benzo[d]isoxazol-3-yloxy)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneA. 4-(Benzo[d]isoxazol-3-yloxy)-piperidine-1-carboxylic acid tert-butylester

To a stirred solution of 263 mg oft-butyl-4-hydroxy-1-piperidinecarboxylate (1.3 mmol) in 5 mL of dry DMFwas added 52 mg of 60% NaH in mineral oil (1.3 mmol). After stirring atroom temperature for 10 min, 100 mg (0.65 mmol) of3-chloro-1,2-benzisoxazole in DMF (1 mL) was added. The mixture wasstirred at 40° C. overnight and then partitioned between EtOAc (50 mL)and water (20 mL) and separated. The aqueous layer was further extractedwith EtOAc (2×30 mL). The combined organic layers were then washed withwater (25 mL), brine, dried over Na₂SO₄, and the solvent was removedunder reduced pressure to give crude product. Purification bychromatography (silica, gradient elution of 40% hexanes/CH₂Cl₂ to 100%CH₂Cl₂) gave 176 mg (85%) product as a light yellow solid. MS(electrospray): exact mass calculated for C₁₇H₂₂N₂O₄, 318.16; m/z found,341.1 [M+Na]⁺. ¹H NMR (CDCl₃, 400 MHz): 7.64 (dt, J=8.02, 1.17 Hz, 1H),7.53 (ddd, J=8.41, 7.04, 1.17 Hz, 1H), 7.43 (dt, J=8.41, 0.78 Hz, 1H),7.27 (ddd, J=8.02, 7.04, 0.78 Hz, 1H), 5.07 (m, 1H), 3.87-3.77 (br m,2H), 3.30 (m, 2H), 2.17-2.10 (br m, 2H), 1.93-1.84 (br m, 2H), 1.48 (s,9H).

B.1-[1-{3-[4-(Benzo[d]isoxazol-3-yloxy)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

A solution of 176 mg (0.55 mmol) of4-(benzo[d]isoxazol-3-yloxy)-piperidine-1-carboxylic acid tert-butylester in CH₂Cl₂(2 mL) was treated with trifluoroacetic acid (0.5 mL) atroom temperature overnight. The solvent was then removed and the crudeproduct dissolved in methanol and stirred over 100 mg of sodiumbicarbonate for 1 h, the solid was then filtered off and the filtrateconcentrated. The crude piperidine was then dissolved in 4 mL EtOH andtreated with 202 mg (0.55 mmol) of1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneThe solution was heated to 60° C. overnight. The solvent was thenremoved by rotary evaporation and the crude product was purified bycolumn chromatography (silica, 0-10% MeOH/EtOAc) to afford 220 mg (68%)of a white solid. MS (electrospray): exact mass calculated forC₃₀H₃₂F₃N₅O₄, 583.24; m/z found, 584.2 [M+H]⁺. ¹H NMR (CDCl₃, 400 MHz, amixture of amide rotamers): 7.77 (d, J=8.22 Hz, 1H), 7.69 (m, 2H),7.66-7.61 (m, 2H), 7.54-7.49 (m, 1H), 7.41 (d, J=8.41 Hz, 1H), 7.28-7.23(m, 1H), 4.93 (br m, 1H), 4.88 and 4.75 (A and B of AB quartet, J=15.65Hz, 1H), 4.65 (br s, 1H), 4.24-4.18 (m, 0.75H), 4.18-4.09 (m, 1.25H),4.07-3.98 (m, 1.5H), 3.91-3.79 (m, 0.5H), 3.79-3.67 (m, 1H) 3.02-2.85(m, 2.4H), 2.85-2.70 (m, 1.6H), 2.61-2.52 (m, 1H), 2.51-2.40 (m, 2H),2.39-2.30 (m, 1H), 2.24-2.12 (br m, 2H), 2.20 (s, 1.5H), 2.16 (s, 1.5H),2.02-1.86 (m, 2H).

Example 15

1-[1-{3-[4-(5-Chloro-benzooxazol-2-yl)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneA. 5-Chloro-2-piperidin-4-yl-benzooxazole

A flask was charged with 1.35 mL (10 mmol) of methyl isonipicotate, 1.43g (10 mmol) of 2-amino-4-chlorophenol, and 5 g of polyphosphoric acid.The flask was then heated to 180° C. for 5 h. The reaction mixture wasthen poured into water while still warm and treated with 50% KOHsolution until pH 12. This was then extracted with CH₂Cl₂ (3×50 mL),then washed with water (25 mL), brine, dried over Na₂SO₄, and thesolvent was removed under reduced pressure to give 1.53 g (57%) of crudeproduct which was used without further purification.

MS (electrospray): exact mass calculated for C₁₂H₁₃ClN₂O, 236.07; m/zfound, 237.1 [M+H]⁺.

B.1-[1-{3-[4-(5-Chloro-benzooxazol-2-yl)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

A solution of 130 mg (0.55 mmol) of5-chloro-2-piperidin-4-yl-benzooxazole was dissolved in 4 mL EtOH andtreated with 100 mg (0.27 mmol) of1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone.The solution was heated to 60° C. overnight. The solvent was thenremoved by rotary evaporation and the crude product was purified bycolumn chromatography (silica, 0-10% MeOH/EtOAc) to afford 156 mg (95%)of a white solid. MS (electrospray): exact mass calculated forC₃₀H₃₁ClF₃N₅O₃, 601.21; m/z found, 602.2 [M+H]⁺. ¹H NMR (CDCl₃, 400 MHz,a mixture of amide rotamers):7.76 (d, J=8.41 Hz, 1H), 7.71 and 7.67 (Aand B of AB quartet, J=8.41 Hz, 2H), 7.65-7.61 (m, 2H), 7.38 (d, J=8.61Hz, 1H), 7.26 (dd, J=8.61, 1.96, 1H), 4.86 and 4.74 (A and B of ABquartet, J=15.65 Hz, 1H), 4.64 (br s, 1H), 4.24-4.10 (m, 2.3H),4.07-3.97 (m, 1.7H), 3.89-3.67 (m, 2H), 3.06-3.00 (m, 1H), 3.00-2.90 (m,2H), 2.90-2.74 (m, 2H), 2.51-2.38 (m, 3H), 2.25-2.10 (m, 2.3H), 2.20 (s,1.5H), 2.15 (s, 1.5H), 2.06-1.83 (m, 2.7H).

Example 16

1-[1-{3-[4-(Benzothiazol-2-ylamino)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneA. 4-(Benzothiazol-2-ylamino)-piperidine-1-carboxylic acid tert-butylester

To a stirred solution of 300 mg (1.77 mmol) of 2-chlorobenzothiazole indry DMF (3.5 mL) was added 2.9 g of cesium carbonate (8.8 mmol) and 535mg of tert-butyl-4-hydroxy-1-piperidinecarboxylate (2.66 mmol). Themixture was stirred at room temperature for 4 h before it waspartitioned between EtOAc (70 mL) and water (30 mL) and separated. Theaqueous layer was further extracted with EtOAc (2×50 mL). The combinedorganic layers were washed with water (25 mL), brine, dried over Na₂SO₄,and the solvent was removed under reduced pressure. Purification byflash chromatography (silica, 0-15% EtOAc/hexanes) afforded 220 mg (37%)of the desired product as a white solid. MS (electrospray): exact masscalculated for C₁₇H₂₃N₃O₂S, 333.15; m/z found, 334.2 [M+H]⁺. ¹H NMR(CDCl₃, 400 MHz): 7.65 (t, J=7.63 2H), 7.36 (ddd, J=8.41, 7.43, 1.37 Hz,1H), 7.22 (dt, J=7.63, 1.17 Hz, 1H), 5,36 (m, 1H), 3.79-3.70 (br m, 2H),3.36 (m, 2H), 2.12-2.04 (br m, 2H), 1.92-1.82 (br m, 2H), 1.48 (s, 9H).

B.1-[1-{3-[4-(Benzothiazol-2-ylamino)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

A solution of 220 mg (0.66 mmol) of4-(benzothiazol-2-ylamino)-piperidine-1-carboxylic acid tert-butyl esterin dichloromethane (2 mL) was treated with trifluoroacetic acid (0.5 mL)at room temperature overnight. The solvent was then removed and thecrude product dissolved in MeOH and stirred over 100 mg of sodiumbicarbonate for 1 h. The solid was filtered off and the filtrateconcentrated. The crude piperidine was then dissolved in 4 mL EtOH andtreated with 220 mg (0.60 mmol) of1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone.The solution was heated to 60° C. overnight. The solvent was thenremoved by rotary evaporation and the crude product was purified bycolumn chromatography (silica, 0-10% MeOH/EtOAc) to afford 240 mg (66%)of a white solid. MS (electrospray): exact mass calculated forC₃₀H₃₃F₃N₆O₂S: 598.23; m/z found, 599.3 [M+H]⁺. ¹H NMR (CDCl₃, 400 MHz,a mixture of amide rotamers): 7.78 (d, J=8.22 Hz, 1H), 7.72 and 7.68 (Aand B of AB quartet, J=8.41 Hz, 2H), 7.64 (d, J=8.22 Hz, 1H), 7.56 (bd,J=8.02 Hz, 1H), 7.51 (bd, J=8.02 Hz, 1H), 7.29 (bd, J=7.63 Hz, 1H), 7.08(bt, J=7.63 Hz, 1H), 5.29 (br s, 1H), 4.88 and 4.75 (A and B of ABquartet, J=15.65 Hz, 1H), 4.65 (br s, 1H), 4.23-4.16 (m, 1H), 4.16-4.08(m, 1H), 4.06-3.98 (m, 2H), 3.92-3.65 (m, 3H), 3.03-2.70 (m, 4H),2.52-2.41 (m, 3H), 2.26-2.18 (m, 1H), 2.21 (s, 1.5H), 2.16 (s, 1.5H),2.16-2.08 (m, 2H), 1.66-1.44 (m, 2H).

Example 17

1-[1-{3-[4-(3,5-Dichloro-pyridin-4-yloxy)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneA. 4-(3,5-Dichloro-pyridin-4-yloxy)-piperidine-1-carboxylic acidtert-butyl ester

To a stirred solution of 828 mg (4.12 mmol) oftert-butyl-4-hydroxy-1-piperidinecarboxylate in 10 mL of dry DMF wasadded 165 mg of 60% NaH in mineral oil (4.12 mmol). After stirring atroom temperature for 10 min, 500 mg (2.74 mmol) of3,4,5-trichloropyridine was added. The mixture was stirred at 80° C.overnight and then partitioned between EtOAc (50 mL) and water (20 mL)and separated. The aqueous layer was further extracted with EtOAc (2×30mL). The combined organic layers were washed with water (25 mL), brine,dried over Na₂SO₄, and the solvent was removed under reduced pressure.Column chromatography (silica, 60-100% CH₂Cl₂/hexanes) gave 265 mg (28%)of desired product. MS (electrospray): exact mass calculated forC₁₅H₂₀Cl₂N₂O₃, 346.09; m/z found, 369.1 [M+Na]⁺. ¹H NMR (CDCl₃, 400MHz): 8.45 (s, 2H), 4.66 (m, 1H), 3.90-3.80 (br m, 2H), 3.26 (m, 2H),1.96-1.83 (br m, 4H), 1.47 (s, 9H).

B.1-[1-{3-[4-(3,5-Dichloro-pyridin-4-yloxy)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

A solution of 103 mg (0.30 mmol) of4-(3,5-dichloro-pyridin-4-yloxy)-piperidine-1-carboxylic acid tert-butylester in CH₂Cl₂ (2 mL) was treated with trifluoroacetic acid (0.5 mL) atroom temperature overnight. The solvent was then removed and the crudeproduct dissolved in MeOH and stirred over 100 mg of sodium bicarbonatefor 1 h. The solid was filtered off and the filtrate concentrated. Thecrude piperidine was then dissolved in 4 mL EtOH and treated with 100 mg(0.27 mmol) of1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone.The solution was heated to 60° C. overnight. The solvent was thenremoved by rotary evaporation and the crude product was purified bycolumn chromatography (silica, 0-10% MeOH/EtOAc) to afford 90 mg (54%)of a white solid. MS (electrospray): exact mass calculated forC₂₈H₃₀Cl₂F₃N₅O₃, 611.17; m/z found, 612.2 [M+H]⁺. ¹H NMR (CDCl₃, 400MHz, a mixture of amide rotamers): 8.44 (s, 2H), 7.77 (d, J=8.41 Hz,1H), 7.72 and 7.68 (A and B of AB quartet, J=8.41 Hz, 2H), 7.65 (d,J=8.41 Hz, 1H), 4.88 and 4.76 (A and B of AB quartet, J=15.65 Hz, 1H),4.66 (br s, 1H), 4.55 (br s, 1H), 4.26-4.08 (m, 2H), 4.08-3.98 (m, 2H),3.91-3.69 (m, 2H), 3.03-2.92 (m, 1.6H), 2.91-2.85 (m, 0.8H), 2.85-2.75(m, 1.6H), 2.52-2.40 (m, 3H), 2.35-2.24 (br m, 1H), 2.22 (s, 1.5H), 2.17(s, 1.5H), 2.03-1.90 (m, 4H).

Example 18

1-[1-{3-[4-(1H-Benzoimidazol-2-yl)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneA. 2-Piperidin-4-yl-1H-benzoimidazole

A flask was charged with 1.35 mL (10 mmol) of methyl isonipicotate, 1.0g (10 mmol) of 1,2-phenylenediamine and 5 g of polyphosphoric acid. Theflask was then heated to 180° C. for 5 h. The reaction mixture was thenpoured into water while still warm and treated with 50% KOH solutionuntil pH 12. This was then extracted with CH₂Cl₂ (3×50 mL), washed withwater (25 mL), brine, dried over Na₂SO₄, and the solvent was removedunder reduced pressure to give 530 mg (27%) of crude product which wasused without further purification. MS (electrospray): exact masscalculated for C₁₂H₁₅N₃, 201.13; m/z found, 202.1 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆):12.1 (br s, 1H), 7.49 (br m, 1H), 7.38 (br m, 1H), 7.09(br m, 2H), 3.00 (dt, J=12.13, 3.33 Hz, 2H), 2.88 (tt, J=11.54, 3.74 Hz,1H), 2.57 (dt, J=12.13, 2.35 Hz, 2H), 1.90 (m, 2H), 1.66 (m, 2H).

B.1-[1-{3-[4-(1H-Benzoimidazol-2-yl)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

A solution of 83 mg (0.41 mmol) of 2-piperidin-4-yl-1H-benzoimidazolewas dissolved in 4 mL EtOH and treated with 100 mg (0.27 mmol) of1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone.The solution was heated to 60° C. overnight. The solvent was thenremoved by rotary evaporation and the crude product was purified bycolumn chromatography (silica, 0-10% MeOH/EtOAc) to afford 55 mg (36%)of a white solid. MS (electrospray): exact mass calculated forC₃₀H₃₃F₃N₆O₂, 566.26; m/z found, 567.3 [M+H]⁺. ¹H NMR (CDCl₃, 400 MHz, amixture of amide rotamers):10.66 (br s, 0.5H), 10.57 (br s, 0.5H), 7.73(bd, J=8.41 Hz, 1H), 7.72-7.63 (m, 3H), 7.60 (bd, J=8.41 Hz, 1H),7.39-7.32 (m, 1H), 7.23-7.13 (m, 2H), 7.02 (br s, 1), 4.86 and 4.75 (Aand B of AB quartet, J=15.85 Hz, 1.25H), 4.64 (br s, 1H), 4.21-4.06 (m,2H), 4.06-3.81 (m, 2H), 3.80-3.63 (m, 1H), 3.80-3.69 (m, 1H), 3.00-2.68(m, 5H), 2.44-2.36 (m, 2H), 2.39-2.23 (m, 2H), 2.19 (s, 1.6H), 2.15 (s,1.4H), 2.13-2.00 (m, 4H), 2.00-1.80 (m, 2H).

Example 19

6-Chloro-4-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-benzo[1,4]oxazin-3-oneA.5-Methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(10.0 g, 29.0 mmol) and epichlorohydrin (24 mL, 307 mmol) were setstirring in DMF (150 mL) containing Cs₂CO₃ (10.4 g, 31.9 mmol). Afterstirring at room temperature for 4 days the mixture was evaporated,brought up in EtOAc and washed with water. The organics were dried(MgSO₄) and evaporated to give a light yellow solid. Columnchromatography (silica, 5% acetone/CH₂Cl₂) gave 4.1 g (35%) of a whitesolid. TLC (silica, 5% acetone/CH₂Cl₂): R_(f)=0.28. MS (electrospray):exact mass calculated for C₁₇H₁₈F₃N₃O₃S, 401.10; m/z found, 402.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃); 7.84 (d, J=8.3 Hz, 2H), 7.79 (d, J=8.3Hz, 2H), 4.70-4.62 (m, 3H), 4.25 (d, J=5.4 Hz, 1H), 3.90-3.70 (m, 2H),3.47 (m, 1H), 3.10-2.9 (m, 6H), 2.65-2.60 (m, 1H).

B. 4-(5-Chloro-2-hydroxy-phenylamino)-piperidine-1-carboxylic acidtert-butyl ester

2-Amino-4-chloro-phenol (30.0 g, 209 mmol) and4-oxo-piperidine-1-carboxylic acid tert-butyl ester (46.0 g, 231 mmol)were set stirring in dichloromethane (600 mL). Sodiumtriacetoxyborohydride (58.0 g, 274 mmol) was added in portions over 10min. Acetic acid (12 mL, 210 mmol) was then added and the mixture leftto stir for 18 h. Saturated NaHCO₃ was added and the organics seperated.The organics were dried (MgSO₄) and evaporated to give 56 g (82%) of alight beige solid. TLC (silica, 50% EtOAc/hexanes): R_(f)=0.66. MS(electrospray): exact mass calculated for C₁₆H₂₃ClN₂O₃, 326.14; m/zfound, 349.1 [M+Na]⁺. ¹H NMR (400 MHz, DMSO-d₆): 6.70 (d, J=8.3 Hz, 1H),6.63 (s, 1H), 6.47 (d, J=8.2 Hz, 1H), 3.97 (d, J=12.2 Hz, 2H), 3.55-3.50(m, 1H), 2.93 (br s, 2H), 1.93 (d, J=11.1 Hz, 2H), 1.48 (s, 9H), 1.35(d, J=11.2 Hz, 2H).

C.4-[(5-Chloro-2-hydroxy-phenyl)-ethoxycarbonylmethyl-amino]-piperidine-1-carboxylicacid tert-butyl ester

4-(5-Chloro-2-hydroxy-phenylamino)-piperidine-1-carboxylic acidtert-butyl ester (15.6 g, 47.7 mmol) was set stirring in THF (200 mL)and cooled to 5° C. Sodium hydride (1.37 g, 54.2 mmol) was added inportions over 10 min and the mixture left to stir for 1 h. Ethylbromoacetate (5.8 mL, 52.3 mmol) was added and the ice bath removed.After stirring for 20 h the mixture was evaporated, brought up in EtOAcand washed with water. The organics were dried (MgSO₄) and evaporated togive 22.5 g of a deep red oil. The oil was purified (silica, 5%acetone/CH₂Cl₂) to give 12.9 g (65%) of a clear orange liquid. TLC(silica, 5% acetone/CH₂Cl₂): R_(f)=0.43. MS (electrospray): exact masscalculated for C₂₀H₂₉ClN₂O₅, 412.18; m/z found, 413.2 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 6.75-6.62 (m, 3H), 4.71 (s, 1H), 4.37 (q, J=7.2 Hz,2H), 4.14 (br s, 2H), 3.55-3.50 (m, 1H), 3.08 (br t, 2H), 2.14 (m, 2H),1.65-1.45 (m, 12H), 1.41 (t, J=7.2 Hz, 3H).

D.4-(6-Chloro-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-piperidine-1-carboxylicacid tert-butyl ester

4-[(5-Chloro-2-hydroxy-phenyl)-ethoxycarbonylmethyl-amino]-piperidine-1-carboxylicacid tert-butyl ester (12.9 g, 31.2 mmol) was set stirring in MeOH (100mL). A solution of NaOH (2.5 g, 62.5 mmol) in water (100 mL) was addedand the mixture stirred at room temperature for 3 h. The mixture wasacidified to pH 2 and MeOH evaporated. The aqueous layer was extractedtwice with EtOAc. The organics were combined, dried (MgSO₄) andevaporated to give 11 g of a clear orange oil. The oil was set stirringin CH₂Cl₂ (150 mL) and EDC (8.2 g, 42.8 mmol) was added. After 1 h theorganics were washed with 1 N HCl (100 mL), water (100 mL) and dried(MgSO₄). The solvent was evaporated to give 7.2 g (63%) of a clearorange solid. TLC (silica, 5% acetone/CH₂Cl₂): R_(f)=0.53. MS(electrospray): exact mass calculated for C₁₈H₂₃ClN₂O₄, 366.13; m/zfound, 389.1 [M+Na]⁺. ¹H NMR (400 MHz, CDCl₃): 7.19 (s, 1H), 7.11-7.00(m, 2H), 4.60 (s, 2H), 4.50-4.30 (m, 3H), 3.00-2.80 (m, 2H), 2.70-2.60(m, 2H), 1.86 (d, J=11.4 Hz, 2H), 1.60 (s, 9H).

E. 6-Chloro-4-piperidin-4-yl-4H-benzo[1,4]oxazin-3-one

4-(6-Chloro-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-piperidine-1-carboxylicacid tert-butyl ester (7.2 g, 19.6 mmol) was set stirring and a 1:1TFA/CH₂Cl₂ solvent mixture was added. After 1 h the mixture wasevaporated under reduced pressure and the resulting red oil brought upin Et₂O. A solid formed and was filtered and air dried to give 7.2 g(96%) of a light beige solid. MS (electrospray): exact mass calculatedfor C₁₃H₁₅ClN₂O₂, 266.08; m/z found, 267.1 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): 7.52 (s, 1H), 7.20-7.00 (m, 2H), 4.60 (s, 2H), 4.50-4.40 (m,1H), 3.65-3.55 (m, 2H), 3.28 (t, J=13.1 Hz, 2H), 3.10-3.00 (m, 2H), 2.15(d, J=13.9 Hz, 2H).

F.6-Chloro-4-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-benzo[1,4]oxazin-3-one

6-Chloro-4-piperidin-4-yl-4H-benzo[1,4]oxazin-3-one (252 mg, 0.66 mmol)and5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(209 mg, 0.52 mmol) were set stirring in EtOH (10 mL) containing Et₃N(115 μL, 0.83 mmol) at 70° C. After 2 days the mixture was cooled,evaporated, brought up in EtOAc and washed with saturated NaHCO₃. Theorganics were dried (MgSO₄) and evaporated to give a clear golden oil.The oil was purified (silica, 50% acetone/CH₂Cl₂) to give 191 mg (55%)of a white solid. TLC (silica, 50% acetone/CH₂Cl₂): R_(f)=0.38. MS(electrospray): exact mass calculated for C₃₀H₃₃ClF₃N₅O₅S, 667.18; m/zfound, 668.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.83 (d, J=8.3 Hz, 2H),7.77 (d, J=8.3 Hz, 2H), 7.21 (s, 1H), 7.10-7.00 (m, 2H), 4.68 (d, J=5.1Hz, 2H), 4.58 (s, 2H), 4.40-4.10 (m, 4H), 3.90-3.70 (s, 2H), 3.30-3.0(m, 4H), 3.00 (s, 3H), 2.90-2.70 (m, 2H), 2.65-2.50 (m, 3H), 2.35-2.20(m, 2H), 1.88 (d, J=11.3 Hz, 2H).

Example 20

6-Chloro-1-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-oneA. 3-(2-Amino-5-chloro-phenyl)-acrylic acid ethyl ester

2-Amino-5-chlorobenzaldehyde (7.58 g, 48.7 mmol) and 36 g (103 mmol) of(carbethoxymethylene)triphenylphosphorane were added in benzene (300 mL)and heated to reflux for 20 h. The reaction mixture was cooled andconcentrated to give an orange oil. The oil was brought up in Et₂O andprecipitated appeared. This was filtered and washed with Et₂O. Theorganics were evaporated to give a clear orange oil. The oil waspurified by column chromatography (silica, 10-40% EtOAc/hexanes) toobtain 10.4 g (95%) of a yellow solid. MS (electrospray): exact masscalculated for C₁₁H₁₂ClNO₂, 225.06; m/z found, 226.1 [M⁺+H]. ¹H NMR (400MHz, CDCl₃): 7.69 (d, J=15.85 Hz, 1H), 7.30 (d, J=2.54 Hz, 1H), 7.07(dd, J=6.26 Hz, 2.35 Hz, 1H), 6.60 (d, J=8.61 Hz, 1H), 6.30 (d, J=15.85Hz, 1H), 4.22 (dd, J=7.24 Hz, 7.24 Hz, 2H), 3.98 (br s, 2H), 1.30 (t,J=7.04 Hz, 3H).

B.4-[4-Chloro-2-(2-ethoxycarbonyl-vinyl)-phenylamino]-piperidine-1-carboxylicacid tert-butyl ester

3-(2-Amino-5-chloro-phenyl)-acrylic acid ethyl ester (10.4 g, 46 mmol)and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (13.8 g, 69mmol) were set stirring in CH₂Cl₂ (230 mL). Sodium triacetoxyborohydride(14.6 g, 69 mmol) was added in portions over 10 min. Acetic acid (1.3mL, 25 mmol) was then added and the mixture left to stir. After 18 hsaturated NaHCO₃ was added and the organics separated. The organics weredried over Na₂SO₄ and concentrated. The residue was purified by columnchromatography (silica, 20-50% EtOAc/hexanes) to obtain 12.4 g (66%) ofa light beige solid. TLC (silica, 25% EtOAc/hexanes): R_(f)=0.5. MS(electrospray): exact mass calculated for C₂₁H₂₉ClN2O₄, 408.18; m/zfound, 409.1 [M⁺+H]. ¹H NMR (400 MHz, CDCl₃): 7.64 (d, J=15.65 Hz, 1H),7.29 (d, J=2.35 Hz, 1H), 7.14 (dd, J=6.26 Hz, 2.54 Hz, 1H), 6.59 (d,J=9.00 Hz, 1H), 6.28 (d, J=15.65 Hz, 1H), 4.23 (dd, J=7.04 Hz, 7.04 Hz,2H), 4.11-3.98 (m, 2H), 3.81 (br s, 1H), 3.46-3.36 (m, 1H), 2.89 (t,J=11.74 Hz, 2H), 2.04-1.95 (m, 2H), 1.44 (s, 9H), 1.42-1.33 (m, 2H),1.30 (t, J=7.24 Hz, 3H).

C.4-[4-Chloro-2-(2-ethoxycarbonyl-ethyl)-phenylamino]-piperidine-1-carboxylicacid tert-butyl ester

4-[4-Chloro-2-(2-ethoxycarbonyl-vinyl)-phenylamino]-piperidine-1-carboxylicacid tert-butyl ester (12.4 g, 30.4 mmol) in EtOAc (150 mL) containingPtO₂ (1 g) was placed on a Parr hydrogenator at 60 psi H₂. After 18 hthe mixture was filtered through celite and evaporated to give a clearbrown liquid. The liquid was purified by column chromatography (silica,20-50% EtOAc/hexanes) to obtain 5.7 g (46%) of the title compound. TLC(silica, 25% EtOAc/hexanes): R_(f)=0.5. MS (electrospray): exact masscalculated for C₂₁H₃₁ClN₂O₄, 410.2; m/z found, 411.2 [M⁺+H]. ¹H NMR (400MHz, CDCl₃): 7.05 (dd, J=6.06 Hz, 2.54 Hz, 1H), 6.99 (d, J=2.35 Hz, 1H),6.55 (d, J=8.61 Hz, 1H), 4.13 (dd, J=7.04 Hz, 3.13 Hz, 2H), 4.11-3.98(m, 2H), 3.81 (br s, 1H), 3.72 (t, J=6.26 Hz, 2H), 3.46-3.36 (m, 1H),2.75 (t, J=7.43 Hz, 2H), 2.60 (t, J=7.04, 2H), 2.04-1.95 (m, 2H), 1.46(s, 9H), 1.42-1.33 (m, 2H), 1.26 (t, J=7.24 Hz, 3H).

D. 4-[2-(2-Carboxy-ethyl)-4-chloro-phenylamino]-piperidine-1-carboxylicacid tert-butyl ester

4-[4-Chloro-2-(2-ethoxycarbonyl-ethyl)-phenylamino]-piperidine-1-carboxylicacid tert-butyl ester (5.7 g, 13.9 mmol) was set stirring in MeOH (40mL). A solution of NaOH (1.4 g, 34.7 mmol) in water (10 mL) was addedand the mixture stirred at room temperature. After 3 h the mixture wasacidified to pH 7 and MeOH was evaporated. The aqueous layer wasextracted with CH₂Cl₂ (3×100 mL). The organics were combined, dried overNa₂SO₄ and concentrated to afford 3.9 g (73%) of the desired product.TLC (silica, 50% EtOAc/hexanes): R_(f)=0.4. MS (electrospray): exactmass calculated for C₁₉H₂₇ClN₂O₄, 382.17; m/z found, 381.1 [M⁻−H].

E. 4-(6-Chloro-2-oxo-3,4-dihydro-2H-quinolin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester

4-[2-(2-Carboxy-ethyl)-4-chloro-phenylamino]-piperidine-1-carboxylicacid tert-butyl ester (3.9 g, 10.1 mmol) and EDC (2.9 g, 15.3 mmol) wereset stirring in CH₂Cl₂ (50 mL) for 2 h. The reaction mixture wasdissolved in CH₂Cl₂ (150 mL), washed with water (2×50 mL) and brine(1×50 mL). The organic layer was dried over Na₂SO₄ and concentrated. Theresidue was purified by column chromatography (silica, 30-50%EtOAc/hexanes) to obtain 1.9 g (52%) of the desired product. TLC(silica, 50% EtOAc/hexanes): R_(f)=0.67. MS (electrospray): exact masscalculated for C₁₉H₂₅ClN₂O₃, 364.16; m/z found, 365.1 [M⁺+H]. ¹H NMR(400 MHz, CDCl₃): 7.14-7.08 (m, 2H), 6.98 (d, J=8.61 Hz, 1H), 4.33-3.98(m, 3H), 2.75 (t, J=7.83 Hz, 4H), 2.55-2.36 (m, 4H), 1.70-1.65 (m, 2H),1.44 (s, 9H).

F. 6-Chloro-1-piperidin-4-yl-3,4-dihydro-1H-quinolin-2-one

4-(6-Chloro-2-oxo-3,4-dihydro-2H-quinolin-1-yl)-piperidine-1-carboxylicacid tert-butyl ester (1.2 g, 3.28 mmol) was set stirring in 1:1TFA/CH₂Cl₂. After 45 min the mixture was evaporated and the golden oilbrought up in Et₂O. A solid formed and was filtered, washed with Et₂Oand air dried to give 1.3 g (93%) of a white solid. MS (electrospray):exact mass calculated for C₁₃H₁₇ClN₂O, 264.10; m/z found, 265.1 [M⁺+H].

G.6-Chloro-1-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-one

6-Chloro-1-piperidin-4-yl-3,4-dihydro-1H-quinolin-2-one (270 mg, 0.62mmol) and5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(165 mg, 0.41 mmol) were set stirring in EtOH (10 mL) containing Et₃N(97 μL, 0.70 mmol) at 80° C. After 16 h the mixture was cooled,evaporated, brought up in dichloromethane and washed with water. Theorganics were dried over Na₂SO₄ and concentrated. The residue waspurified by column chromatography (silica, 5-1 0% MeOH/CH₂Cl₂) to obtain205 mg (75%) of a white solid. TLC (silica, 10% MeOH/CH₂Cl₂):R_(f)=0.75. MS (electrospray): exact mass calculated forC₃₁H₃₅ClF₃N₅O₄S, 665.21; m/z found, 666.2 [M⁺+H]. ¹H NMR (CDCl₃, 400MHz): 7.69 (d, J=8.41 Hz, 2H), 7.62 (d, J=8.41 Hz, 2H), 7.16-7.08 (m,2H), 7.00 (d, J=9.00 Hz, 1H), 4.52 (dd, J=14.28 Hz, 5.48 Hz, 2H), 4.18(dd, J=10.56 Hz, 3.13 Hz, 1H), 4.14-4.04 (m, 2H), 4.03-3.96 (m, 1H),3.72-3.56 (m, 2H), 3.10-2.96 (m, 2H), 2.95-2.86 (m, 2H), 2.85 (s, 3H),2.75 (t, J=6.26 Hz, 2H), 2.69-2.54 (m, 2H), 2.53-2.47 (m, 2H), 2.44-2.31(m, 3H), 2.15-2.05 (m, 1H), 1.71-1.62 (m, 2H).

Example 21

6-Chloro-1-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinazolin-2-oneA. Spiro[piperidine-4,2′(1′H)-6′-chloro-3′,4′-dihydro-4′-oxo-quinazoline]-1-carboxylic acid tert-butyl ester

To a stirred solution of 2-amino-5-chlorobenzamide (5.67 g, 33.2 mmol)and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (6.62 g, 33.2mmol) in benzene (70 mL) was added a catalytic amount (˜0.3 g) ofp-toluenesulfonic acid. The mixture was heated to reflux for 20 h undera Dean-Stark trap. The resulting suspension was concentrated. SaturatedNaHCO₃ (68 mL) was added. The mixture was extracted with EtOAc and theprecipitated crystals in the aqueous layer was collected by filtration.The solid was washed with water and dried to afford 11.22 g (96%) of thedesired product. MS (electrospray): exact mass calculated forC₁₇H₂₂ClN₃O₃, 351.13; m/z found, 352.1 [M⁺+H]. ¹H NMR (CD₃OD, 400 MHz):7.50 (d, J=2.54 Hz, 1H), 7.13 (dd, J=6.06 Hz, 2.54 Hz, 1H), 6.65 (d,J=8.61 Hz, 1H), 3.56-3.47 (m, 2H), 3.36-3.25 (m, 2H), 1.79-1.66 (m, 4H),1.32 (s, 9H).

B. 4-(2-Aminomethyl-4-chloro-phenylamino)-piperidine-1-carboxylic acidtert-butyl ester

Spiro[piperidine-4,2′(1′H)-6′-chloro-3′,4′-dihydro-4′-oxo-quinazoline]-1-carboxylic acid tert-butyl ester (1 g,2.8 mmol) and borane-tetrahydrofurane complex (1.0 M, 9.9 mL, 9.9 mmol)were added in THF (10 mL) and heated to reflux for 6 h. The reactionmixture was cooled and poured into ice water. The resulting suspensionwas extracted with CH₂Cl₂ (2×100 mL). The organics were dried andconcentrated. The residue was purified by column chromatography (silica,5-10% MeOH/CH₂Cl₂) to obtain 795 mg (79%) of the product. MS(electrospray): exact mass calculated for C₁₇H₂₆ClN₃O₂, 339.17; m/zfound, 362.1 [M⁺+Na]. ¹H NMR (CDCl₃, 400 MHz): 7.07 (dd, J=6.06 Hz, 2.54Hz, 1H), 6.97 (d, J=2.54 Hz, 1H), 6.54 (d, J=8.61 Hz, 1H), 3.94-3.70 (m,4H), 3.48-3.38 (m, 1H), 3.05 (t, J=11.15 Hz, 2H), 2.68-2.55 (m, 1H),2.02-1.90 (m, 4H), 1.46 (s, 9H).

C.4-(6-Chloro-2-oxo-3,4-dihydro-2H-quinazolin-1-yl)-piperidine-1-carboxylicacid tert-butyl ester

1,1′-Carbonyldiimidazole (0.51 g, 3.15 mmol) was added to a solution of4-(2-aminomethyl-4-chloro-phenylamino)-piperidine-1-carboxylic acidtert-butyl ester (0.79 g, 2.25 mmol) in CH₃CN (10 mL) over 3 h withstirring at 50° C. The reaction mixture was then cooled to roomtemperature and stirred for additional 2 h. The reaction mixture wasdissolved in CH₂Cl₂ (100 mL), washed with water (2×10 mL), brine (1×10mL). The organic layer was dried over Na₂SO₄ and concentrated. Theresidue was purified by column chromatography (silica, 30-50%EtOAc/hexanes) to obtain 0.46 g (63%) of the desired product. TLC(silica, 50% EtOAc/hexanes): R_(f)=0.5. MS (electrospray): exact masscalculated for C₁₈H₂₄ClN₃O₃, 365.15; m/z found, 388.1 [M⁺+Na]. ¹H NMR(CDCl₃, 400 MHz): 7.18 (dd, J=6.26 Hz, 2.54 Hz, 1H), 7.05 (d, J=2.15 Hz,1H), 6.94 (d, J=9.00 Hz, 1H), 6.29 (s, 1H), 4.32-4.18 (m, 4H), 4.13-4.02(m, 1H), 2.88-2.71 (m, 2H), 2.64-2.50 (m, 2H), 1.82-1.73 (m, 2H), 1.49(s, 9H).

D. 6-Chloro-1-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one

4-(6-Chloro-2-oxo-3,4-dihydro-2H-quinazolin-1-yl)-piperidine-1-carboxylicacid tert-butyl ester (0.52 g, 1.42 mmol) was set stirring in 1:1TFA/CH₂Cl₂. After 45 min the mixture was evaporated and the golden oilbrought up in Et₂O. A solid formed and was filtered, washed with Et₂Oand air dried to give 0.52 g (97%) of an off-white solid. MS(electrospray): exact mass calculated for C₁₃H₁₆ClN₃O, 265.10; m/zfound, 266.1 [M⁺+H].

E.6-Chloro-1-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinazolin-2-one

6-Chloro-1-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (183 mg, 0.42mmol) and5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(112 mg, 0.28 mmol) were set stirring in EtOH (10 mL) containing Et₃N(66 μL, 0.47 mmol) at 80° C. After 16 h the mixture was cooled,evaporated, brought up in CH₂Cl₂ and washed with water. The organicswere dried over Na₂SO₄ and concentrated. The residue was purified bycolumn chromatography (silica, 5-10% MeOH/CH₂Cl₂) to obtain 141 mg (76%)of a white solid. TLC (silica, 10% MeOH/CH₂Cl₂): R_(f)=0.6. MS(electrospray): exact mass calculated for C₃₀H₃₄ClF₃N₆O₄S, 666.20; m/zfound, 667.2 [M⁺+H]. ¹H NMR (CDCl₃, 400 MHz): 7.70 (d, J=7.83 Hz, 2H),7.63 (d, J=8.02 Hz, 2H), 7.12 (dd, J=6.65 Hz, 2.35 Hz, 1H), 7.01 (br s,1H), 6.92 (d, J=9.00 HZ, 1H), 5.44 (br s, 1H), 4.54 (dd, J=14.67 Hz,6.46 Hz, 2H), 4.23-4.08 (m, 4H), 4.05-3.97 (m, 1H), 3.92-3.80 (m, 1H),3.74-3.57 (m, 2H), 3.14-2.99 (m 2H), 2.97-2.87 (m, 2H), 2.86 (s, 3H),2.78-2.57 (m, 2H), 2.48-2.32 (m, 3H), 2.10 (t, J=11.50 Hz 1H), 1.80-1.70(m, 2H).

Example 22

1-[4-(6-Chloro-2,2-dioxo-3,4-dihydro-2H-2λ⁶-benzo[1,2,6]thiadiazin-1-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-olA.4-(6-Chloro-2,2-dioxo-3,4-dihydro-2H-2λ⁶-benzo[1,2,6]thiadiazin-1-yl)-piperidine-1-carboxylicacid tert-butyl ester

A solution of4-(2-aminomethyl-4-chloro-phenylamino)-piperidine-1-carboxylic acidtert-butyl ester (678 mg, 2 mmol) and sulfamide (596 mg, 6.2 mmol) inpyridine (12 mL) was heated to reflux for 6 h. The reaction mixture wasthen cooled to room temperature and poured into ice water (50 mL). Thesolution was extracted with CH₂Cl₂ (4×100 mL). The organic extracts wasdried over Na₂SO₄ and concentrated. The residue was purified by columnchromatography (silica, 30-50% EtOAc/hexanes) to obtain 767 mg (96%) ofthe desired product. TLC (silica, 50% EtOAc/hexanes): R_(f)=0.75. MS(electrospray): exact mass calculated for C₁₇H₂₄ClN₃O₄S, 401.12; m/zfound, 400.1 [M⁻−H]. ¹H NMR (CDCl₃, 400 MHz): 7.13 (dd, J=6.46 Hz, 2.15Hz, 1H), 7.00 (d, J=1.96 Hz, 1H), 6.92 (d, J=8.60 Hz, 1H), 5.54 (br s,1H), 4.35 (s, 2H), 4.11-3.81 (m, 3H), 2.62 (br s, 2H), 1.90-1.66 (m,4H), 1.34 (s, 9H).

B. 6-Chloro-1-piperidin-4-yl-3,4-dihydro-1H-benzo[1,2,6]thiadiazine2,2-dioxide

4-(6-Chloro-2,2-dioxo-3,4-dihydro-2H-216-benzo[1,2,6]thiadiazin-1-yl)-piperidine-1-carboxylicacid tert-butyl ester (767 mg, 1.91 mmol) was set stirring in 1:1TFA/CH₂Cl₂. After 45 min the mixture was evaporated and the golden oilbrought up in Et₂O. A solid formed and was filtered, washed with Et₂Oand air dried to give 730 mg (91%) of an off-white solid. MS(electrospray): exact mass calculated for C₁₂H₁₆ClN₃O₂S, 301.07; m/zfound, 302.0 [M⁺+H].

C.1-[4-(6-Chloro-2,2-dioxo-3,4-dihydro-2H-2λ⁶-benzo[1,2,6]thiadiazin-1-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol

6-Chloro-1-piperidin-4-yl-3,4-dihydro-1H-benzo[1,2,6]thiadiazine2,2-dioxide (440 mg, 1.03 mmol) and5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(415 mg, 1.03 mmol) were set stirring in EtOH (20 mL) containing Et₃N(215 μL, 1.54 mmol) at 80° C. After 16 h the mixture was cooled,evaporated, brought up in CH₂Cl₂ and washed with water. The organicswere dried over Na₂SO₄ and concentrated. The residue was purified bycolumn chromatography (silica, 0-5% MeOH/CH₂Cl₂) to obtain 229 mg (32%)of a white solid. TLC (silica, 5% MeOH/CH₂Cl₂): R_(f)=0.8. MS(electrospray): exact mass calculated for C₂₉H₃₄ClF₃N₆O₅S₂, 702.17; m/zfound, 703.2 [M⁺+H]. ¹H NMR (CDCl₃, 400 MHz, a mixture of two rotamers):7.66 (d, J=8.61 Hz, 2H), 7.60 (d, J=8.61 Hz, 2H), 7.16 (dd, J=6.85 Hz,1.96 Hz, 1H), 6.98 (s, 1H), 6.95 (d, J=9.00 HZ, 1H), 4.47 (s, 2H), 4.33(s, 2H), 4.16-3.99 (m, 2H), 3.98-3.90 (m, 1H), 3.89-3.78 (m, 1H),3.62-3.52 (m, 2H), 3.05-2.95 (m, 1H), 2.93-2.84 (m, 2H), 2.82 (s, 3H),2.81-2.76 (m, 1H), 2.33 (d, J=6.46 Hz, 2H), 2.25 (t, J=11.24 Hz, 1H),2.09-1.90 (m, 3H), 1.90-1.78 (m, 2H).

Example 23

4-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-pyrido[3,2-b][1,4]oxazin-3-oneA. 4-(3-Hydroxy-pyridin-2-ylamino)-piperidine-1-carboxylic acidtert-butyl ester

To a stirring solution of 4.7 g (0.042 mol) of 2-amino-3-hydroxypyridineand 12.75 g (0.064 mol) of 4-oxo-piperidine-1-carboxylic acid tert-butylester in CH₂Cl₂/AcOH (150 mL/60 mL) was added 10 g (0.070 mol) ofNa₂SO₄. After 3.5 h, 9.9 g (0.047) of sodium triacetoxyborohydride wasadded in three portions, and the mixture was stirred at room temperaturefor 15 h. The reaction was then quenched with NaHCO₃ (150 mL), extractedwith CH₂Cl₂ (500 mL), washed with NaHCO₃ (2×100 mL), and the combinedaqueous layers were extracted with EtOAc (150 mL). The combined organiclayers were dried over Na₂SO₄, concentrated, and purified using flashchromatography (silica, 3-10% MeOH/CH₂Cl₂) to afford 5.9 g (48%) of abeige powder. MS (electrospray): exact mass calculated for C₁₅H₂₃N₃O₃,293.17; m/z found, 294.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.52 (dd,J=5.3 Hz, 1.3 Hz, 1H), 6.79 (dd, J=7.6 Hz, 1.3 Hz, 1H), 6.40 (dd, J=7.6Hz, 5.3 Hz, 1H), 4.06-3.94 (m, 3H), 3.02-2.86 (m, 2H), 2.72 (br s, 1H),2.06-1.97 (m, 2H), 1.42 (s, 9H), 1.46-1.28 (m, 2H).

B. 4-(3-Ethoxycarbonylmethoxy-pyridin-2-ylamino)-piperidine-1-carboxylicacid tert-butyl ester

A stirring solution of 1.4 g (0.0048 mol) of4-(3-hydroxy-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butylester was dissolved in THF (24 mL) was cooled to 0° C., and 0.13 g(0.0052 mol) of NaH was added. After 30 min, 0.8 g (0.0052 mol) of ethylbromoacetate was added, and reaction was allowed to warm to roomtemperature and stirred overnight. Saturated NaHCO₃ (20 mL) was addedand the reaction mixture was partitioned between EtOAc (200 mL) andsaturated NaHCO₃ (75 mL). The organic layer was washed with water (50mL) and NaCl (50 mL), dried over Na₂SO₄, and concentrated to afford 0.9g (49%) of a white powder. MS (electrospray): exact mass calculated forC₁₉H₂₉N₃O₅, 379.21; m/z found, 380.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):7.74 (d, J=5.3 Hz, 1H), 6.76 (d, J=7.8 Hz, 1H), 6.46 (dd, J=7.8 Hz, 5.3Hz, 1H), 5.05 (d, J=7.33 Hz, 1H), 4.59 (s, 2H), 4.26 (q, J=7.3 Hz, 2H),4.18-3.92 (m, 3H), 2.97 (t, J=11.6 Hz, 2H), 2.06 (d, J=12.1 Hz, 2H),1.46 (s, 9H), 1.46-1.34 (m, 2H) 1.29 (t, J=7.3 Hz, 3H).

C.4-(3-Oxo-2,3-dihydro-pyrido[3,2-b][1,4]oxazin-4-yl)-piperidine-1-carboxylicacid tert-butyl ester

To a stirring solution of 0.9 g (0.0023 mol) of4-(3-ethoxycarbonylmethoxy-pyridin-2-ylamino)-piperidine-1-carboxylicacid tert-butyl ester in H₂O/MeOH (1 mL/11 mL) was added 0.05 g (0.0023mol) of LiOH. After 6 h, the solvent was removed under reduced pressure.The residue was dissolved in DMF (12 mL) and to the stirring solutionwas added 1.82 g (0.0048 mol) of HATU. After 3 h, the reaction waspartitioned between EtOAc (250 mL) and saturated NaHCO₃ (100 mL), andwashed with water (3×100 mL). The combined aqueous layers were extractedwith EtOAc (100 mL). The combined organic layers were washed with brine(100 mL), dried over Na₂SO₄, and concentrated to afford 0.37 g (46%) ofa white solid. MS (electrospray): exact mass calculated for C₁₇H₂₃N₃O₄,333.17; m/z found, 356.1 [M+Na]⁺. ¹H NMR (400 MHz, CDCl₃): 7.97 (dd,J=4.8 Hz, 1.5 Hz, 1H), 7.25 (dd, J=8.1 Hz, 1.5 Hz, 1H), 6.96 (dd, J=8.1Hz, 4.8 Hz, 1H), 5.03 (tt, J=11.9 Hz, 4.0 Hz, 1H), 4.55 (s, 2H), 4.13 d,J=10.9 Hz, 2H), 2.82-2.69 (m, 2H), 2.68 (qd, J=12.4 Hz, 4.0 Hz, 2H),1.65 (d, J=12.1 Hz, 2H), 1.46 (s, 9H).

D. 4-Piperidin-4-yl-4H-pyrido[3,2-b][1,4]oxazin-3-one

To a stirring solution of 0.37 g (0.0011 mol) of4-(3-oxo-2,3-dihydro-pyrido[3,2-b][1,4]oxazin-4-yl)-piperidine-1-carboxylicacid tert-butyl ester in CH₂Cl₂ (2.5 mL) was added 2.5 mL of TFA. After2.5 h, the solvent was removed. The residue was partitioned betweenEtOAc (200 mL) and 1 N NaOH (150 mL). The aqueous layer was extractedwith EtOAc (3×100 mL) and the combined organic layers were dried overNa₂SO₄, and concentrated to afford 0.24 g (94%) of a white/pink solid.¹H NMR (400 MHz, CDCl₃): 7.87 (dd, J=4.8 Hz, 1.5 Hz, 1H), 7.25 (dd,J=7.8 Hz, 1.8 Hz, 1H), 6.84 (dd, J=7.8 Hz, 4.8 Hz, 1H), 4.98-4.83 (m,1H), 4.45 (s, 2H), 3.90 (s, 1H), 3.06 (d, J=8.3 Hz, 2), 2.65-2.53 (m,4H), 1.65-1.53 (m, 2H).

E.4-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl-propyl}-piperidin-4-yl)-4H-pyrido[3,2-b][1,4]oxazin-3-one

To a stirring solution of 0.24 g (0.001 mol) of4-piperidin-4-yl-4H-pyrido[3,2-b][1,4]oxazin-3-one inEtOH/Dichloroethane (2 mL/2 mL) was added 0.27 g (0.0007 mol) of5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoro-methyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine.The reaction mixture was heated to 80° C. and stirred for 16 h. Thesolvent was then removed under reduced pressure, and the crude productwas purified using flash chromatography (30% acetone/CH₂Cl₂), affording0.42 g (96%) of a white solid. MS (electrospray): exact mass calculatedfor C₂₉H₃₃F₃N₆O₅S, 634.22; m/z found, 635.3 [M+H]⁺. ¹H-NMR (400 MHz,CDCl₃): 8.00 (dd, J=4.8 Hz, 1.5 Hz, 1H), 7.71 and 7.67 (A and B ofAA′BB′ quartet, J_(ab)=8.4 Hz, 4H), 7.22 (dd, J=7.9 Hz, 1.5 Hz, 1H),6.94 (dd, J=7.9 Hz, 4.8 Hz, 1H), 4.94 (tt, J=12.1 Hz, 4.0 Hz, 1H) 4.57and 4.55 (A and B of AB quartet, J_(ab)=14.5 Hz, 2H), 4.57 (s, 2H),4.25-4.02 (m, 3H), 3.78-3.61 (m, 2H), 3.16-2.90 (m, 4H), 2.90 (s, 3H),2.89-2.76 (m, 1H), 2.56-2.43 (m, 3H) 2.23 (t, J=11.2 Hz, 1H), 1.67 (d,J=11.3 Hz, 2H).

Example 24

5-Chloro-1-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-oneA. 2-(5-Chloro-2-nitro-phenyl)-malonic acid diethyl ester

Sodium hydride (2.94 g, 123 mmol) was set stirring in DMSO (100 mL) andheated to 100° C. Diethyl malonate (17.5 mL, 115 mmol) in DMSO (30 mL)was added and after 10 min a clear red solution was obtained.2,4-Dichloronitrobenzene in DMSO (50 mL) was added. After 1.5 h themixture was cooled and added to water (1000 mL). The product wasextracted with ether. The organics were dried (MgSO₄) and evaporated toa clear yellow oil (10 g, 59%). TLC (silica, 20% EtOAc/hexanes):R_(f)=0.36. MS (electrospray): exact mass calculated for C₁₃H₁₄ClNO₆,315.05; m/z found, 338.0 [M+Na]⁺. ¹H NMR (400 MHz, CDCl₃): 8.05 (d,J=8.7 Hz, 1H), 7.55-7.40 (m, 2H), 5.30 (s, 1H), 4.30 (q, J=7.1 Hz, 4H),1.31 (t, J=7.1 Hz, 6H).

B. (5-Chloro-2-nitro-phenyl)-acetic acid ethyl ester

2-(5-Chloro-2-nitro-phenyl)-malonic acid diethyl ester (10.3 g, 32.6mmol) in DMSO (200 mL) containing LiCl (2.9 g, 68.4 mmol) and water (0.6mL, 33.3 mmol) was set stirring and heated to 100° C. After 5 h themixture was cooled to room temperature and added to water (750 mL). Theproduct was extracted with two portions of EtOAc. The organics werecombined, washed with water, dried (MgSO₄) and evaporated to give 5.9 g(75%) of a clear yellow oil. TLC (silica, 25% EtOAc/hexanes):R_(f)=0.50. ¹H NMR (400 MHz, CDCl₃): 8.21 (d, J=8.8 Hz, 1H), 7.56 (dd,J=8.8, 2.3 Hz, 2H), 7.47 (d, J=2.3 Hz, 1H), 4.30 (q, J=7.2 Hz, 2H), 4.12(s, 2H), 1.38 (t, J=7.1 Hz, 3H).

C. (2-Amino-5-chloro-phenyl)-acetic acid ethyl ester

(5-Chloro-2-nitro-phenyl)-acetic acid ethyl ester (5.9 g, 24.2 mmol) inbenzene (125 mL) containing PtO₂ (500 mg) was placed on a Parrhydrogenator at 40 psi H₂. After 18 h the mixture was filtered throughcelite and evaporated to give a clear brown liquid. The liquid waspurified (silica, 25% EtOAc/hexanes) to give 3.3 g (64%) of a cleargolden liquid. TLC (silica, 25% EtOAc/hexanes): R_(f)=0.30. MS(electrospray): exact mass calculated for C₁₀H₁₂ClNO₂, 213.06; m/zfound, 214.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.20-7.10 (m, 2H), 6.78(d, J=8.3 Hz, 1H), 4.26 (q, J=7.2, 2H), 1.18 (t, J=7.1 Hz, 3H).

D. 4-(5-Chloro-2-oxo-2,3-dihydro-indol-1-yl)-piperidine-1-carboxylicacid tert-butyl ester

(2-Amino-5-chloro-phenyl)-acetic acid ethyl ester (3.3 g, 15.4 mmol),4-oxo-piperidine-1-carboxylic acid tert-butyl ester (4.6 g, 23 mmol)were set stirring in CH₂Cl₂ (50 mL) and sodium triacetoxyborohydride(4.9 g, 23.1 mmol) was added followed by acetic acid (3 mL). After 5days saturated NaHCO₃ was added and the organics separated. The organicswere dried (MgSO₄) and evaporated to give 7.5 g of a clear golden oil.The oil was purified (silica, 50% EtOAc/hexanes) to give 3.4 g (63%) ofa white solid. TLC (silica, 25% EtOAc/hexanes): R_(f)=0.18. MS(electrospray): exact mass calculated for C₁₈H₂₃ClN₂O₃, 350.14; m/zfound, 373.1 [M+Na]⁺. ¹H NMR (400 MHz, CDCl₃): 7.40-7.30 (m, 2H), 7.00(d, J=8.4 Hz, 1H), 4.55-4.45 (m, 1H), 4.40 (m, 2), 3.63 (s, 2H), 2.94(m, 2H), 2.45-2.30 (m, 2H), 1.82 (m, 2H), 1.62 (s, 9H).

E. 5-Chloro-1-piperidin-4-yl-1,3-dihydro-indol-2-one

4-(5-Chloro-2-oxo-2,3-dihydro-indol-1-yl)-piperidine-1-carboxylic acidtert-butyl ester (3.4 g, 9.7 mmol) was set stirring in 1:1 TFA/CH₂Cl₂.After 45 min the mixture was evaporated and the golden oil brought up inEt₂O. A solid formed and was filtered, washed with Et₂O and air dried togive 3.4 g (97%) of a white solid. MS (electrospray): exact masscalculated for C₁₃H₁₅ClN₂O, 250.09; m/z found, 251.1 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆); 7.45 (s, 2H), 7.31 (d, J=8.1 Hz, 1H), 4.55-4.45 (m, 1H),3.68 (s, 2H), 3.50 (d, J=12.3, 2H), 3.14 (m, 2H), 2.70-2.55 (m, 2H),1.87 (d, J=13.1 Hz, 2H).

F.5-Chloro-1-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-one

5-Chloro-1-piperidin-4-yl-1,3-dihydro-indol-2-one (256 mg, 0.70 mmol)and5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(255 mg, 0.64 mmol) were set stirring in EtOH (15 mL) containing Et₃N(107 □L, 0.77 mmol) at 80° C. After 20 h the mixture was cooled,evaporated, brought up in CH₂Cl₂ and washed with water. The organicswere dried (MgSO₄) and evaporated to give a clear golden oil. The oilwas purified (silica, 50% acetone/CH₂Cl₂) to give 225 mg (54%) of awhite solid. TLC (silica, 50% acetone/CH₂Cl₂): R_(f)=0.32. MS(electrospray): exact mass calculated for C₃₀H₃₃ClF₃N₅O₄S, 651.19; m/zfound, 652.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.82 (d, J=8.1 Hz, 2H),7.76 (d, J=8.1 Hz, 2H), 7.40-7.25 (m, 2H), 7.04 (d, J=8.1 Hz, 2H), 4.66(d, J=4.0 Hz, 2H), 4.40-41.0 (m, 4H), 4.05-3.70 (m, 3H), 3.59 (s, 2H),3.30-3.0 (m, 4H), 2.99 (s, 3H), 2.70-2.40 (m, 5H), 2.28 (m, 2H).

Example 25

1-[4-(6-Chloro-indol-1-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-olA. 5-Chloro-2-(2,2-dimethoxy-ethyl)-phenylamine

To a stirred solution of 10.3 g (60 mmol) of 4-chloro-2-nitrotoluene indry DMF (120 mL) was added 16.45 g of N,N-dimethylformamidedimethylacetal (138 mmol). The mixture was heated to 140° C. for 18 hafter which the solvent was removed under reduced pressure and theresidue diluted with 150 mL of MeOH and 15.2 mL of chlorotrimethylsilane(120 mmol). The reaction mixture was then heated to 60° C. overnight.Methanol was then removed under reduced pressure and the residue wastaken up in EtOH and transferred to a Parr bottle. 100 mg of 10%Platinum on carbon was added and the reaction mixture was put under 2atmospheres of hydrogen on a Parr shaker for 8 h. When the reaction wascompleted the catalyst was removed by filtration and the filtrate wasconcentrated under reduced pressure. The crude aniline was used withoutfurther purification. TLC (silica, 35% EtOAc/hexanes): R_(f)=0.4. MS(electrospray): exact mass calculated for C₁₀H₁₄ClNO₂, 215.07; m/zfound, 216.1 [M+H]⁺.

B.4-[5-Chloro-2-(2,2-dimethoxy-ethyl)-phenylamino]-piperidine-1-carboxylicacid tert-butyl ester

To a stirred solution of 2 g of5-chloro-2-(2,2-dimethoxy-ethyl)-phenylamine, (9.27 mmol) in 50 mL ofacetic acid was added 3.7 g of 4-oxo-piperidine-1-carboxylic acidtert-butyl ester (18.5 mmol). The reaction mixture was allowed to stirfor 1 h at room temperature before the portion wise addition of 5.9 g ofsodium triacetoxyborohydride (27.9 mmol). The reaction mixture wasallowed to stir an additional 5 h before removing the solvent underreduced pressure. The crude product was partitioned between CH₂Cl₂ (250mL) and water. The aqueous layer was further extracted with CH₂Cl₂ (2×75mL). The combined organic layers were then washed with 1 N NaOH (2×50mL), brine, dried over Na₂SO₄, and concentrated. Purification bychromatography (silica, 10-25% EtOAc/hexanes) afforded 1.5 g (71%) ofdesired product. TLC (silica, 35% EtOAc/hexanes): R_(f)=0.49. MS(electrospray): exact mass calculated for C₂₀H₃₁ClN₂O₄, 398.20; m/zfound, 399.2 [M+H]⁺. ¹H NMR (CDCl₃, 400 MHz): 6.94 (d, J=7.83 Hz, 1H),6.61 (dd, J=7.83, 2.02 Hz, 1H), 6.57 (d, J=2.02 Hz, 1H), 4.87 (br s,1H), 4.40 (t, J=5.31 Hz, 1H), 3.97 (br m, 2H), 3.36 (s, 6H), 3.02 (m,2H), 2.78 (d, J=5.05 Hz, 2H), 2.00 (m, 2H), 1.47 (s, 9H), 1.37 (m, 2H).

C. 6-Chloro-1-piperidin-4-yl-1H-indole

To a stirred solution of 1.03 g (2.59 mmol) of4-[5-chloro-2-(2,2-dimethoxy-ethyl)-phenylamino]-piperidine-1-carboxylicacid tert-butyl ester in 15 mL toluene was added 1.0 g (5.2 mmol) ofp-toluenesulfonic acid. The reaction mixture was heated to 60° C. for 20min, allowed to cool to room temperature and quenched with 100 mL ofsat. aqueous NaHCO₃ then extracted with EtOAc (3×75 mL). The combinedorganic layers were washed with brine, dried over Na₂SO₄, andconcentrated to afford 590 mg (98%) of the desired product as a pinkoil. MS (electrospray): exact mass calculated for C₁₃H₁₅ClN₂, 234.09;m/z found, 235.1 [M+H]⁺. ¹H NMR (CDCl₃, 400 MHz, a mixture of amiderotamers): 7.52 (d, J=8.34 Hz, 1H), 7.38 (br s, 1H), 7.21 (d, J=3.28 Hz,1H), 7.06 (dd, J=8.34, 1.77 Hz, 1H), 6.49 (d, J=3.28 Hz, 1H), 4.24 (m,1H), 3.30 (m, 2H), 2.85 (dt, J=12.38, 2.53 Hz, 2H), 2.08 (m, 2H), 1.94(m, 2H).

D.1-[4-(6-Chloro-indol-1-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol

To a stirred solution of 86 mg (0.21 mmol) of5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridinein 4 mL of EtOH was added 50 mg (0.39 mmol) of6-chloro-1-piperidin-4-yl-1H-indole. The solution was heated to 60° C.overnight. The solvent was then removed by rotary evaporation and thecrude product was purified by column chromatography (silica, gradientelution from 0-5% 2 N NH₃/MeOH in CH₂Cl₂) to afford 64 mg (48%) of awhite solid. MS (electrospray), exact mass calculated forC₃₀H₃₃ClF₃N₅O₃S: 635.19; m/z found, 636.2 [M+H]⁺. HPLC (reverse phaseconditions 10-90%), t_(R)=4.88 min. ¹H NMR (CDCl₃, 400 MHz): 7.72 and7.67 (A and B of AB quartet, J=8.80 Hz, 4H), 7.52 (d, J=8.41, 1H), 7.34(s, 1H), 7.18 (d, J=3.33 Hz, 1H), 7.07 (dd, J=8.41, 1.76 Hz, 1H), 6.50(d, J=3.33 Hz, 1H), 4.59 and 4.54 (A and B of AB quartet, J=14.48 Hz,2H), 4.24 (dd, J=13.69, 2.39 Hz, 1H), 4.21-4.14 (m, 2H), 4.05 (dd,J=13.69, 6.46 Hz, 1H), 3.69 (m, 2H), 3.15 (br d, J=11.54 Hz, 1H),3.11-2.91 (m, 3H), 2.60-2.48 (m, 3H), 2.28 (dt, J=11.74, 2.15 Hz, 1H),2.13-1.93 (m, 4H).

Example 26

1-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1H-benzotriazole

To a stirred solution of3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propionaldehyde(0.084 g, 0.21 mmol) in CH₂Cl₂ (0.5 mL) were added1-piperidin-4-yl-1H-benzotriazole hydrochloride (Maybridge Chemicals,0.050 g, 0.21 mmol), Et₃N (0.1 mL) and glacial AcOH (12 □L, 0.21 mmol)in that order and stirred for 20 min. NaBH(OAc)₃ (0.058 g, 0.27 mmol)was added and stirred under nitrogen overnight. Saturated NaHCO₃ (1 mL)was added and stirred for 30 min. The layers were separated and theaqueous layer was extracted with CH₂Cl₂ (3 mL). The combined organicextracts were washed with brine (3 mL), dried over Na₂SO₄, and removedunder reduced pressure. MPLC of the crude afforded the desired compoundas a white solid (0.098 g, 80%). TLC (silica, 12% MeOH/CH₂Cl₂):R_(f)=0.44. MS (electrospray): exact mass calculated for C₂₈H₃₂F₃N₇O₂S,587.23; m/z found 588.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.00 (d, J=8.4Hz, 1H), 7.66 (d, J=8.2 Hz, 2H), 7.59 (d, J=8.2 Hz, 2H), 7.50 (d, J=8.4Hz, 1H), 7.41 (dt, J=0.9, 7.6 Hz, 1H), 7.30 (dt, J=0.9, 7.6 Hz, 1H) 4.59(br t, J=11.2 Hz, 1H), 4.50 (s, 2H), 4.10 (t, J=6.7 Hz, 2H), 3.63 (t,J=5.8 Hz, 2H), 3.00 (br d, J=12.0 Hz, 2H), 2.89 (t, J=5.8 Hz, 2H), 2.86(s, 3H), 2.38-2.27 (m, 4H), 2.17-1.99 (m, 6H).

Example 27

1-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-sulfonicacid amide A.1-(3-Oxo-propyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester

Dess-Martin periodinane (1.43 g, 3.36 mmol) was added portion wise to astirred solution of1-(3-hydroxy-propyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester (1.30 g, 3.05 mmol) in CH₂Cl₂ (15 mL) at 0° C.under N₂. Then the reaction was stirred at 0° C. for 15 min and allowedto warm to room temperature. After stirring at room temperature for 1.5h the reaction was diluted with Et₂O (50 mL) and saturated NaHCO₃ (15mL) was added slowly (caution! gas evolution). Then Na₂S₂O₃.5H₂O (5.31g, 21.4 mmol) was added and stirred for 30 min. The layers wereseparated and the aqueous layer was extracted with Et₂O (2×30 mL). Thecombined extracts were washed with brine, dried (Na₂SO₄) andconcentrated. MPLC (1-10% MeOH/CH₂Cl₂) afforded the aldehyde in 79%yield (1.02 g). TLC (silica, 10% MeOH/CH₂Cl₂): R_(f)=0.67. MS(electrospray) calculated for C₂₁H₂₄F₃N₃O₃, 424.2 ([M+H]⁺), m/z found,424.2. ¹H NMR (400 MHz, CDCl₃): 9.82 (s, 1H), 7.65 (br d, J=8.0 Hz, 2H),7.54 (br s, 2H), 4.53 (s, 2H), 4.21 (t, J=6.2 Hz, 2H), 3.68 (br s, 2H),3.04 (t, J=6.2 Hz, 2H), 2.70 (t, J=5.6 Hz, 2H), 1.39 (s, 9H).

B.1-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester

To a stirred solution of1-(3-oxo-propyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester (0.99 g, 23.6 mmol) in CH₂Cl₂ (20 mL) were added1-methyl-3-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (0.60 g, 25.9mmol) and glacial AcOH (0.13 mL, 23.6 mmol) in that order and stirredfor 20 min. NaBH(OAc)₃ (0.65 g, 30.6 mmol) was added and stirred undernitrogen for 2 h. Saturated NaHCO₃ (20 mL) was added and stirred for 30min, and the layers were separated. The organic extract was washed withbrine, dried over Na₂SO₄, and concentrated under reduced pressure. MPLCof the crude afforded the desired compound as a white solid (1.27 g,85%). TLC (silica, 7% MeOH/CH₂Cl₂): R_(f)=0.35. MS (electrospray): exactmass calculated for C₃₄H₄₁F₃N₆O₃, 638.32; m/z found, 639.3 [M+H]⁺, 661.2[M+Na]⁺. ¹H NMR (400 MHz, CDCl₃): 7.81 (br d, J=8.0 Hz, 2H), 7.68 (br s,2H), 7.25 (dd, J=1.6, 7.5 Hz, 1H), 7.15-7.07 (m, 2H), 7.02(dd, J=1.6,7.9 Hz, 1H), 4.70 (br s, 2H), 4.38 (tt, J=4.2, 12.4 Hz, 1H), 4.18 (t,J=6.8 Hz, 2H), 3.82 (s, 2H), 3.45 (s, 3H), 3.07 (d, J=11.6 Hz, 2H), 2.84(t, J=5.5 Hz, 2H), 2.53-2.42 (m, 2H), 2.44 (t, J=6.7 Hz, 2H), 2.21-2.03(m, 4H), 1.84 (d, J=12.0 Hz, 2H), 1.52 (s, 9H).

C.1-Methyl-3-(1-{3-[3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one

1-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester (1.19 g, 1.86 mmol) was dissolved intrifluoroacetic acid (5 mL) and CH₂Cl₂ (5 mL) and allowed to stir atroom temperature for 2 h. The reaction mixture was concentrated, dilutedwith CH₂Cl₂, and washed with saturated NaHCO₃. The organic layer wasdried over Na₂SO₄ and concentrated to afford1-methyl-3-(1-{3-[3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one(0.955 g, 96%) as a white foam. TLC (silica, 10% MeOH/CH₂Cl₂):R_(f)=0.19. MS (electrospray) calculated for C₂₉H₃₃F₃N₆O, 539.3([M+H]⁺), m/z found, 539.3.

D.1-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-sulfonicacid (N-t-butoxy carbonyl)amide

To a solution of chlorosulfonyl isocyanate (0.018 mL, 0.209 mmol) inCH₂Cl₂ (0.150 mL) was added 2-methyl-2-propanol (0.020 mL, 0.209 mmol)and the solution was stirred at room temperature for 15 min. Thissolution was then added dropwise to a solution of1-methyl-3-(1-{3-[3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one(75 mg, 0.139 mmol) and triethylamine (0.039 mL, 0.279 mmol) in CH₂Cl₂(0.4 mL). An additional 0.15 mL of CH₂Cl₂ was used to transfer all ofthe material to the reaction mixture. The reaction mixture was allowedto stir overnight. Column chromatography (silica, 2-10% MeOH/CH₂Cl₂)gave 93 mg (93%) of the title compound. TLC (silica, 5% MeOH/CH₂Cl₂):R_(f)=0.24. MS (electrospray): calculated for C₃₄H₄₂F₃N₇O₅S, 718.3([M+H]⁺); m/z found, 718.3.

F.1-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-sulfonicacid amide

1-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-sulfonicacid (N-t-butoxy carbonyl)amide (75 mg, 0.105 mmol) was dissolved intrifluoroacetic acid (0.75 mL) and CH₂Cl₂ (0.75 mL). The reactionmixture was allowed to stir for 2 h, concentrated, diluted with CH₂Cl₂(25 mL) and washed with saturated NaHCO₃. The organic layer was driedover Na₂SO₄, concentrated, and purified by silica gel chromatography(5-10% MeOH/CH₂Cl₂) to afford1-{3-[4-(3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-sulfonicacid amide (15 mg, 23%). MS (electrospray) calculated for C₂₉H₃₄F₃N₇O₃S,618.2 ([M+H]⁺), m/z found, 618.2. ¹H NMR (400 MHz, CDCl₃): 7.72 (d,J=8.2 Hz, 2H), 7.63 (d, J=8.2 Hz, 2H), 7.22 (br s, 1H), 7.04-7.11 (m,2H), 6.95-7.00 (m, 1H), 5.02 (br s, 1H), 4.53 (s, 1H), 4.08-4.36 (m,3H), 3.68 (br t, J=5.9 Hz, 2H), 3.38 (s, 3H), 2.95-3.01 (m, 2H),2.41-2.70 (m, 4H), 2.11-2.34 (m, 4H), 1.52-1.94 (m, 6H).

Example 28

5-Chloro-3-(1-{2-hydroxy-3-[4-pyridin-4-yl-3-(4-trifluoromethyl-phenyl)-pyrazol-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-dihydro-benzoimidazol-2-oneA.4-[1-Oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyridine

To a solution of4-[3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyridine (0.5 g, 1.73mmol) and epichlorohydrin (1.35 mL, 17.3 mmol) in DMF (2 mL) was addedcesium carbonate (0.676 g, 2.07 mmol). The reaction mixture was allowedto stir for 24 h, diluted with EtOAc and washed successively withsaturated NaHCO₃, water, and brine. The organic layer was dried overNa₂SO₄, concentrated and partially purified by running through a plug ofsilica gel (5% acetone/CH₂Cl₂) to afford4-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyridine(0.198 g, 33%) as an unstable oil. TLC (silica, 20% acetone/CH₂Cl₂):R_(f)=0.39. MS (electrospray): exact mass calculated for C₁₈H₁₄F₃N₃O,346.1 [M+H]⁺, m/z found, 346.1.

B.5-Chloro-3-(1-{2-hydroxy-3-[4-pyridin-4-yl-3-(4-trifluoromethyl-phenyl)-pyrazol-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-dihydro-benzoimidazol-2-one

To a solution of4-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyridine(68 mg, 0.197 mmol) and5-chloro-1-methyl-3-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one(0.055 g, 0.207 mmol) in EtOH (1 mL) was added triethylamine (0.027 mL,0.197 mmol). The reaction mixture was heated at 80° C. overnight,concentrated, and purified by column chromatography (silica, 2-10%MeOH/CH₂Cl₂) to afford the title compound (0.026 g, 22%). MS(electrospray): exact mass calculated for C₃₁H₃₀ClF₃N₆O₂, 611.2 [M+H]⁺,m/z found, 611.2. ¹H NMR (400 MHz, CDCl₃): 8.59 (br s, 2H), 8.20 (s,1H), 7.67 (d, J=8.2 Hz, 2H), 7.61 (d, J=5.9 Hz, 2H), 7.55 (d, J=8.2 Hz,2H), 7.35 (br s, 1H), 7.09 (dd, J=8.2, 1.8 Hz, 1H), 6.89 (d, J=8.2 Hz,1H), 4.55-4.60 (m, 2H), 4.39 (d, J=14.2, 4.1 Hz, 1H), 4.31 (d, J=14.2,6.1 Hz, 1H), 3.80-3.90 (m, 2H), 3.37 (s, 3H), 3.18-3.33 (m, 2H),3.02-3.17 (m, 2H), 2.77-2.95 (m, 2H), 1.99 (t, J=12.4 Hz, 2H).

Example 29

4-(1-{2-Hydroxy-3-[4-pyrazin-2-yl-3-(4-trifluoromethyl-phenyl)-pyrazol-1-yl]-propyl}-piperidin-4-yl)-4H-benzo[1,4]oxazin-3-oneA. 4-(2-Hydroxy-phenylamino)-piperidine-1-carboxylic acid tert-butylester

2-Aminophenol (15.0 g, 137 mmol) and 4-oxo-piperidine-1-carboxylic acidtert-butyl ester (27.4 g, 138 mmol) were set stirring in CH₂Cl₂ (200 mL)at room temperature. Sodium triacetoxyborohydride (40.8 g, 193 mmol) wasadded in portions over 10 min followed by acetic acid (7.8 mL, 136mmol). After 18 h saturated NaHCO₃ was added, the organics separated,dried (MgSO₄) and evaporated to give 36.4 g (91%) of a beige solid. TLC(silica, 50% EtOAc/hexanes): R_(f)=0.56. MS (electrospray): exact masscalculated for C₁₆H₂₄N₂O₃, 292.18; m/z found, 315.1 [M+Na]⁺. ¹H NMR (400MHz, CDCl₃): 9.20 (s, 1H), 6.80-6.50 (m, 3H), 6.40 (t, J=6.1 Hz, 1H),4.30 (d, J=8.7 Hz, 1H), 3.88 (d, J=12.6 Hz, 2H), 3.45-3.35 (m, 1H),3.00-2.75 (br s, 2H), 1.88 (d, J=10.5 Hz, 2H), 1.40 (s, 9H), 1.30-1.20.(m, 2H).

B. 4-(2-Ethoxycarbonylmethoxy-phenylamino)-piperidine-1-carboxylic acidtert-butyl ester

A mixture of NaH (1.56 g, 65 mmol) in THF (100 mL) was set stirring andcooled to 5° C. 4-(2-Hydroxy-phenylamino)-piperidine-1-carboxylic acidtert-butyl ester (17.5 g, 60 mmol) in THF (100 mL) was added dropwiseover 30 min. After 2 h ethyl bromoacetate (7.3 mL, 66 mmol) was added.After stirring at room temperature for 24 h saturated NH₄Cl (100 mL) wasadded and the organics evaporated. The aqueous layer was extracted withEtOAc (2×150 mL). The organics were combined, dried (MgSO₄) andevaporated to give 24 g of a deep red liquid. The liquid was purified(silica, 5% acetone/CH₂Cl₂) to give 21.4 g (94%) of a clear orangeliquid. TLC (silica, 5% acetone/CH₂Cl₂): R_(f)=0.48. MS (electrospray):exact mass calculated for C₂₀H₃₀N₂O₅, 378.22; m/z found, 379.2 [M+H]⁺.¹H NMR (400 MHz, DMSO): 7.02 (m, 1H), 6.90-6.70 (m, 3H), 4.74 (s, 2H),4.37 (q, J=7.1 Hz, 2H), 4.13 (br s, 2H), 3.60-3.50 (m, 1H), 3.08 (m,2H), 2.16 (m, 2H), 1.60-1.50 (m, 2H), 1.58 (s, 9H), 1.41 (t, J=7.1 Hz,3H).

C. 4-(2-Carboxymethoxy-phenylamino)-piperidine-1-carboxylic acidtert-butyl ester

4-(2-Ethoxycarbonylmethoxy-phenylamino)-piperidine-1-carboxylic acidtert-butyl ester (21.4 g, 56.5 mmol) was set stirring in MeOH (150 mL).A solution of NaOH (4.5 g, 112.5 mmol) in water (150 mL) was added.After 3 h the mixture was acidified to pH 4 with 6 N HCl. MeOH wasremoved under reduced pressure and the aqueous layer extracted withEtOAc (2×150 mL). The organics were combined, dried (MgSO₄) andevaporated to give 20 g (100%) of a brown solid. MS (electrospray):exact mass calculated for C₁₈H₂₆N₂O₅, 350.18; m/z found, 351.2 [M+H]⁺.

D. 4-(3-Oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-piperidine-1-carboxylicacid tert-butyl ester

4-(2-Carboxymethoxy-phenylamino)-piperidine-1-carboxylic acid tert-butylester (22 g, 63 mmol) was set stirring in CH₂Cl₂ (200 mL). EDC (13 g, 68mmol) was added in one portion. After 30 min 1 N HCl was added. Theorganics were seperated, dried (MgSO₄) and evaporated to give 17 g (81%)of a clear brown oil. TLC (silica, 5% acetone/CH₂Cl₂): R_(f)=0.45. MS(electrospray): exact mass calculated for C₁₈H₂₄N₂O₄, 332.17; m/z found,259.1 [M-BOC+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.30-7.20 (m, 1H), 7.15-7.10(m, 3H), 4.61 (s, 2H), 4.60-4.45 (m, 1H), 4.45-4.30 (br s, 2H), 2.88 (t,J=12.5 Hz, 2H), 2.65 (dd, J=12.6, 4.5 Hz, 2H), 1.87 (d, J=12.4 Hz, 2H),1.60 (s, 9H).

E. 4-Piperidin-4-yl-4H-benzo[1,4]oxazin-3-one

4-(3-Oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-piperidine-1-carboxylic acidtert-butyl ester (17 g, 51 mmol) and 1:1 TFA/CH₂Cl₂ (40 mL) werecombined and set stirring. After 45 min the mixture was evaporated togive a clear brown oil. The oil was set stirring and Et₂O was added (300mL). A solid formed and was filtered, washed with Et₂O and air dried togive 16 g (90%) of a light beige solid. MS (electrospray): exact masscalculated for C₁₃H₁₆N₂O₂, 232.12; m/z found, 233.1 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): 7.44 (dd, J=6.5, 1.4 Hz, 1H), 7.20-7.7.10 (m, 3H), 4.58 (s,2H), 4.55-4.45 (m, 1H), 4.65-4.55 (m, 2H), 3.27 (dt, J=13.0, 2.3 Hz,2H), 3.05 (dd, J=12.3, 4.1 Hz, 2H), 2.15 (d, J=13.8 Hz, 2H).

F.2-[1-Oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyrazine

To a solution of2-[3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyrazine (200 mg, 0.69mmol) and epichlorohydrin (0.540 mL, 6.9 mmol) in DMF (2 mL) was addedcesium carbonate (450 mg, 1.38 mmol). The reaction mixture was allowedto stir for 24 h, diluted with EtOAc, and washed with saturated NaHCO₃,water, and brine. The organic layer was dried over Na₂SO₄, concentratedand purified by column chromatography (silica, 5% acetone/CH₂Cl₂) toafford2-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyrazine(141 mg, 59%). TLC (silica, 20% acetone/CH₂Cl₂): R_(f)=0.38. MS(electrospray) m/z 347.1 (347.1, calculated for C₁₇H₁₃F₃N₄O, M⁺+H). ¹HNMR (400 MHz, CDCl₃): 8.51 (dd, J=2.8, 1.8 Hz, 1H), 8.45 (d, J=1.5 Hz,1H), 8.38 (d, J=12.8 Hz, 1H), 8.01 (s, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.62(d, J=8.6 Hz, 1H), 4.57 (dd, J=14.7, 3.1 Hz, 1H), 4.21 (dd, J=14.7, 6.1Hz, 1H), 3.44 (m, 1H), 2.91 (t, J=4.5 Hz, 1H), 2.62 (dd, J=4.0, 2.5 Hz,1H).

G.4-(1-{2-Hydroxy-3-[4-pyrazin-2-yl-3-(4-trifluoromethyl-phenyl)-pyrazol-1-yl]-propyl}-piperidin-4-yl)-4H-benzo[1,4]oxazin-3-one

To a solution of2-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyrazine(76 mg, 0.220 mmol) and 4-piperidin-4-yl-4H-benzo[1,4]oxazin-3-one (61mg, 0.231 mmol) in EtOH (1.1 mL) was added triethylamine (0.031 mL,0.220 mmol). The reaction mixture was heated to 80° C. overnight,concentrated, and purified by column chromatography (silica, 5-10%MeOH/CH₂Cl₂) to afford4-(1-{2-hydroxy-3-[4-pyrazin-2-yl-3-(4-trifluoromethyl-phenyl)-pyrazol-1-yl]-propyl}-piperidin-4-yl)-4H-benzo[1,4]oxazin-3-one(27 mg, 21%). TLC (silica, 5% MeOH/CH₂Cl₂): R_(f)=0.09. MS(electrospray): m/z 579.2 (579.2, calculated for C₃₀H₂₉F₃N₆O₃, M⁺+H). ¹HNMR (400 MHz, CDCl₃): 8.53 (s, 1H), 8.48 (s, 1H), 8.40 (s, 1H), 8.11 (s,1H), 7.73 (d, J=8.2 Hz, 2H), 7.63 (d, J=8.2 Hz, 2H), 7.16 (d, J=5.4 Hz,1H), 7.00-7.03 (m, 3H), 4.49 (s, 2H), 4.39 (d, J=10.8 Hz, 1H), 3.13 (d,J=11.9 Hz, 1H), 2.96 (d, J=11.9 Hz, 1H), 2.59-2.80 (m, 2H), 2.40-2.55(m, 3H), 2.17 (t, J=11.9 Hz, 1H), 1.77 (d, J=11.9 Hz, 2H).

Example 30

(S)-1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-oneA. 4-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acidtert-butyl ester

1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (7.24 g, 34.1 mmol) anddi-tert-butyl dicarbonate (9.12 g, 41.0 mmol) were combined in DMF (80mL) and the mixture heated to 40° C. under N₂ for 17 h. The mixture wasallowed to cool, diluted with EtOAc (800 mL) and washed with saturatedNaHCO₃ (150 mL), H₂O (3×150 mL) and brine (150 mL). The combined aqueouswashes were extracted with EtOAc (2×150 mL). The combined extracts weredried over Na₂SO₄ and concentrated, to give4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acidtert-butyl ester (12.36 g, 94%). TLC (silica, 50% EtOAc/hexanes):R_(f)=0.3. MS (electrospray): exact mass calculated for C₁₇H₂₃N₃O₃,340.16; m/z found, 340.1 [M+Na]⁺. ¹H NMR (CDCl₃, 400 MHz): 10.59 (s,1H), 7.15-7.11 (m, 2H), 7.08-7.02 (m, 2H), 4.49 (tt, J=8.4, 4.0 Hz, 1H),4.32 (br s, 2H), 2.89 (br t, J=11.6, 2H), 2.34 (dq, J=12.6, 4.4 Hz, 2H),1.83 (br d, J=10.5 Hz, 2H) 1.36 (s, 9H).

B. 1-Methyl-3-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one

A solution of KHMDS (5.07 g, 25.4 mmol) in THF (40 mL plus a 1.0 mLrinse) was added via cannula to a solution of4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acidtert-butyl ester (6.64 g, 20.2 mmol) in THF (20 mL). The mixture wasstirred for 25 min then iodomethane (5.2 mL, 84 mmol) was added. Theresulting mixture was stirred for 45 min then diluted with EtOAc (700mL). The EtOAc was washed with H₂O (3×200 mL), saturated NaHCO₃ (150 mL)and brine (150 mL). The combined washes were extracted with EtOAc (2×150mL). The combined extracts were dried over Na₂SO₄ and concentrated. Thecrude reaction mixture was purified by column chromatography (silica,15-60% EtOAc/hexanes) to give the methylated adduct (5.21 g, 78%). Thepurified material was dissolved in a mixture of CH₂Cl₂ (40 mL) and TFA(35 mL). The mixture was stirred for 4 h then concentrated in vacuo. Theresidue was dissolved in CH₂Cl₂ (300 mL) and washed with saturatedNaHCO₃ (100 mL). The aqueous layer was extracted with 5% MeOH/CH₂Cl₂(4×150 mL). The combined extracted were dried over Na₂SO₄ andconcentrated to yield the title compound (3.85 g, containing inorganicsalts) which was suitable for further use. TLC (silica, 5% MeOH/CH₂Cl₂):R_(f)=0.1. MS (electrospray): exact mass calculated for C₁₃H₁₈N₃O,232.14; m/z found 232.1 [M+H]⁺. ¹H NMR (CDCl₃, 400 Hz): 7.27-7.29 (m,1H), 7.05-7.12 (m, 2H), 6.99 (dd, J=6.1, 2.1 Hz, 1H), 4.45 (tt, J=12.5,4.2 Hz, 1H), 3.42 (s, 3H), 3.27 (dd, J=10.2, 2.1 Hz, 2H), 2.81 (dt,J=2.4, 12.4 Hz, 2H), 2.35 (dq, J=12.5, 4.2 Hz, 2H), 2.26 (br s, 1H),1.83 (dd, J=12.1, 2.1 Hz, 2H).

C. (R)-tert-Butyl-dimethyl-oxiranylmethoxy-silane

tert-Butyl-chloro-dimethylsilane (12.9 g, 85.5 mmol) followed by Et₃N(19 mL, 136 mmol) was added to a 0° C. solution of (S)-(+)-glycidol (5.0g, 67 mmol) in CH₂Cl₂ (200 mL). The solution was allowed to warm to 23°C. with stirring over 17 h. The resulting pink solution was diluted withEt₂O (800 mL) and stirred an additional 30 min. The Et₂O layer waswashed with saturated aqueous NaHCO₃ (200 mL), H₂O (2×100 mL), brine(100 mL), dried over Na₂SO₄ and concentrated. Purification by columnchromatography (silica, 5-10% Et₂O/hexanes) gave(R)-tert-Butyl-dimethyl-oxiranylmethoxy-silane (10.01 g, 79%). TLC(silica, 10% Et₂O/hexanes): R_(f)=0.5. ¹H NMR (CDCl₃, 400 MHz): 3.85(dd, J=11.9, 3.2 Hz, 1H), 3.66 (dd, J=11.9, 4.8 Hz, 1H), 3.09 (m, 1H),2.77 (dd, J=5.0, 4.2 Hz, 1H), 2.64 (dd, J=5.2, 2.7 Hz, 1H), 0.90 (s,9H), 0.08 (s, 3H), 0.07 (s, 3H).

D.(R)-3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propane-1,2-diol

Cs₂CO₃ (1.88 g, 5.77 mmol) was added to a solution of(R)-tert-Butyl-dimethyl-oxiranylmethoxy-silane (2.72 g, 14.4 mmol) and5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(1.70 g, 4.81 mmol) in DMF (13 mL). The mixture ws stirred at roomtemperature for 5 days, then partitioned between EtOAc (400 mL) andsaturated NaHCO₃ (100 mL). The EtOAc layer was washed with H₂O (3×75 mL)and brine (100 mL), dried over Na₂SO₄ and concentrated. The residue wasdissolved in MeOH (125 mL) and treated with CSA (800 mg). The mixturewas stirred for 20 h then concentrated. The residue was re-dissolved inEtOAc (200 mL), washed with saturated NaHCO₃ (100 mL), dried over Na₂SO₄and concentrated. Purification by column chromatography (silica, 20-60%acetone/CH₂Cl₂) gave the corresponding diol (0.78 g, 40%). TLC (25%acetone/CH₂Cl₂): R_(f)=0.2. MS (electrospray): exact mass calculated forC₁₇H₂₁F₃N₃O₄S, 420.11; m/z found, 420.1 [M+H]⁺. ¹H NMR (CD₃OD/CDCl₃, 400MHz): 7.74 and 7.67 (A and B of AA′BB′, J_(ab)=8.3 Hz, 4H), 4.52 (s,2H), 4.23 (dd, J=13.0, 3.0 Hz, 1H), 4.04-4.11 (m, 2H), 3.64 (t, J=5.9Hz, 2H), 3.52 and 3.57 (A and B of ABX, J_(ab)=11.4, J_(ax)=4.8,J_(bx)=4.9 Hz, 2H), 2.98 (m, 2H), 2.91 (s, 3H).

E.(R)-5-Methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

PpTs (271 mg, 1.1 mmol) and(R)-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propane-1,2-diol(317 mg, 0.756 mmol) were combined in trimethylorthoacetate (30 mL). Themixture was stirred for 18 h then diluted with EtOAc (125 mL), washedwith saturated NaHCO₃ (2×50 mL), brine (50 mL), dried over Na₂SO₄ andconcentrated. Purification by chromatography (silica, 100% EtOAc) gavethe corresponding orthoacetate (313 mg, 0.678 mmol). The purifiedorthoacetate was dissolved in CH₂Cl₂ (2.25 mL), cooled to 0° C., andtreated with MeOH (25 μL) and AcBr (110 μL, 1.48 mmol). The mixture wasallowed to warm over 3 h, then partitioned between EtOAc (50 mL) andsaturated NaHCO₃ (20 mL). The EtOAc layer was washed with saturatedNaHCO₃ (2×20 mL). The combined washes were extracted with EtOAc (3×20mL). The combined extracts were dried over Na₂SO₄ and concentrated. Theresidue was dissolved in EtOH (40 mL) and treated with KOEt (1.0 mL, 40wt % solution in EtOH). After 1 h the mixture was concentrated to ca. 20mL and worked up as above. Purification by column chromatography(silica, 100% EtOAc) gave the epoxide (189 mg, 62%). TLC (100% EtOAc):R_(f)=0.35. MS (electrospray): exact mass calculated for C₁₇H₁₉F₃N₃O₃S,402.10; m/z found, 402.1 M+H]⁺. ¹H NMR (CDCl₃, 400 MHz): 7.72 and 7.67(A and B of AA′BB′, J_(ab)=8.3 Hz, 4H), 4.57 and 4.53 (A and B of AB,J_(ab)=12.9 Hz, 2H), 4.52 (dd, J=15.2, 2.7 Hz, 1H), 4.12 (dd, J=15.2,5.4 Hz, 1H), 3.67 (m, 2H), 3.36 (m, 1H), 2.92 (m, 2H), 2.88 (s, 3H),2.85 (dd, J=4.4, 4.3 Hz, 1H), 2.49 (dd, J=4.6, 2.6 Hz, 1H).

F.(S)-1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl[-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-one

A solution of(R)-5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(134 mg, 0.334 mmol) and1-methyl-3-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (110 mg, 0.476mmol) in EtOH (0.8 mL) and dichloroethane (0.8 mL) was heated to 80° C.for 18 h. The mixture was then concentrated and the residue purified bycolumn chromatography (silica, 0-50% acetone/CH₂Cl₂) to give the titlecompound (134 mg, 86%). TLC (20% acetone/CH₂Cl₂) R_(f)=0.3. MS(electrospray): calculated for C₃₀H₃₆F₃N₆O₄S, [M+H]⁺633.24; m/z found,633.3. ¹H NMR (CDCl₃, 400 MHz): 7.72 and 7.66 (A and B of AA′BB′,J_(ab)=8.3 Hz, 4H), 7.15 (dd, J=7.0, 1.7 Hz, 1H ), 7.08 (m, 2H), 6.98(dd, J=6.6, 1.8 Hz, 1H), 4.60 and 4.55(A and B of AB, J_(ab)=14.5 Hz,2H), 4.34 (m, 1H), 4.23 (dd, J=13.8, 2.8 Hz, 1H), 4.15 (m, 1H), 4.23(dd, J=13.8, 6.6 Hz, 1H), 3.71 (m, 2H), 3.40 (s, 3H), 3.08 (m, 2H), 2.96(m, 2H), 2.89 (s, 3H), 2.56-2.36 (m, 4H), 2.23 (d, J=11.6 Hz, 1H), 1.81(m, 2H).

Example 31

(S)-5-Dimethylamino-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-oneA. 4-(6-Chloro-3-nitro-pyridin-2-ylamino)-piperidine-1-carboxylic acidtert-butyl ester

A stirring solution of 20 g (0.10 mol) of 2,6-dichloro-3-nitro-pyridinein DMF (245 mL) was cooled to 0° C. After 5 min, 9.87 g (0.05 mol) of4-amino-piperidine-1-carboxylic acid tert-butyl ester and 6.8 g (0.05mol) of K₂CO₃ were added, resulting in a suspension. The mixture wasallowed to stir for 5 h at 0° C. The mixture was then partitionedbetween water (300 mL) and EtOAc (400 mL). The aqueous layer was thenextracted with EtOAc (5×400 mL). The organic layer was dried overanhydrous Na₂SO₄, and concentrated to give a brown oil. The product waspurified using silica gel chromatography (silica, 100% CH₂Cl₂, then 10%EtOAc/hexanes) to afford 8.99 g (51%) of the desired product as a brightyellow solid. MS (electrospray): exact mass calculated for C₁₅H₂₁ClN₄O₄,356.13; m/z found, 379.1 [M+Na]⁺. ¹H NMR (400 MHz, CDCl₃): 8.36 (d,J=8.4 Hz, 1H), 8.27 (d, J=7.3 Hz, 1H), 6.62 (d, J=8.4 Hz, 1H), 4.38-4.26(m, 1H), 4.14-3.96 (m, 2H), 3.01 (t, J=11.6 Hz, 2H), 2.05 (dd, J=12.4Hz, 3.03 Hz, 2H), 1.58-1.44 (m, 2H), 1.47 (s, 9H).

B. 4-(6-Dimethylamino-3-nitro-pyridin-2-ylamino)-piperidine-1-carboxylicacid tert-butyl ester

To a stirring solution of 6 g (0.016 mol) of4-(6-chloro-3-nitro-pyridin-2-ylamino)-piperidine-1-carboxylic acidtert-butyl ester in MeOH/CH₂Cl₂ (84 mL/15 mL) was added 2.2 g (0.05 mol)of dimethylamine in THF (25 mL). The reaction mixture was stirred atroom temperature for 16 h, and was then concentrated. The crude productwas then dissolved in CH₂Cl₂ (400 mL) and washed with saturated NaHCO₃(2×200 mL). The washes were combined and extracted with EtOAc (100 mL).The combined organic layers were dried over Na₂SO₄ and concentrated toafford 6.1 g (99%) of the desired product as a bright yellow solid. MS(electrospray): exact mass calculated for C₁₇H₂₇N₅O₄, 365.21; m/z found,388.19 [M+Na]⁺. ¹H NMR (400 MHz, CDCl₃): 8.74 (d, J=7.07 Hz, 1H), 8.18(d, J=9.4 Hz, 1H), 5.97 (d, J=7.3 Hz, 1H), 4.28-4.16 (m, 1H), 4.07-3.93(m, 2H), 3.17 (s, 6H), 3.01 (t, J=11.9 Hz, 2H), 2.05 (dd, J=12.4 Hz and3.03 Hz, 2H), 1.60-1.50 (m, 2H), 1.47 (s, 9H).

C.4-(5-Dimethylamino-1-methyl-2-oxo-1,2-dihydro-imidazo[4,5-b]pyridin-3-yl)-piperidine-1-carboxylicacid tert-butyl ester

A stirring solution of 5.3 g (0.014 mol) of4-(6-dimethylamino-3-nitro-pyridin-2-ylamino)-piperidine-1-carboxylicacid tert-butyl ester in methanol/EtOAc (73 mL/15 mL) was degassed. 10%Pd/C (1.17 g, 0.5 mmol) was added as a suspension in EtOH (5 mL),followed by ammonium formate (4.5 g, 0.073 mol). The mixture was stirredat room temperature for 3 h. The reaction mixture was then filteredthrough celite and the filtrate was concentrated, giving a purple oil.The residue was then dissolved in THF (73 mL), and 11.7 g (0.073 mol) ofCDI was added, and the reaction was heated to 98° C. and stirred for 16h. The mixture was then cooled and concentrated. The crude product wasthen partitioned between EtOAc (800 mL) and NaHCO₃ (100 mL), and theorganic layer was washed with water (5×100 mL) and NaCl (100 mL). Thecombined aqueous layers were back-extracted with EtOAc (150 mL). Theresulting organic layers were combined and dried over Na₂SO₄ andconcentrated. The residue (2.4 g) was dissolved in THF (73 mL). To thisstirring solution was added KHMDS (3.46 g, 0.017 mol) and iodomethane(10.3 g, 0.072 mol), and the mixture was allowed to stir for 20 min. Thesolvent was then concentrated, and the crude product was partitionedbetween EtOAc (600 mL) and NaHCO₃ (200 mL). The organic layer was washedwith NaHCO₃ (150 mL), dried over Na₂SO₄, and concentrated. Purificationusing flash chromatography (silica, 80% EtOAc/hexanes) afforded 2.4 g(67% yield, 3 steps, based upon using ⅔ material at methylation stage)of desired product as a white solid. MS (electrospray): exact masscalculated for C₁₉H₂₉N₅O₃, 375.23; m/z found, 276.17 [M+H-100]⁺. ¹H NMR:(400 MHz, CDCl₃): 7.02 (d, J=8.6 Hz, 1H), 6.15 (d, J=8.6 Hz, 1H), 4.46(tt, J=12.0 Hz and 4.0 Hz, 1H), 4.38-4.11 (m, 2H), 3.33 (s, 3H), 3.01(s, 6H), 2.95-2.73 (m, 2H), 2.73-2.55 (m, 2H), 1.77-1.61 (m, 2H), 1.47(s, 9H).

D.5-Dimethylamino-1-methyl-3-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

To a stirring solution of 1.07 g (0.0028 mol) of4-(5-dimethylamino-1-methyl-2-oxo-1,2-dihydro-imidazo[4,5-b]pyridin-3-yl)-piperidine-1-carboxylicacid tert-butyl ester in CH₂Cl₂ (7 mL) was added 7 mL of TFA. After 35min, the solvent was removed. The residue was partitioned between EtOAc(200 mL) and 1 N NaOH (150 mL). The aqueous layer was extracted withEtOAc (3×100 mL) and the combined organic layers were dried over Na₂SO₄and concentrated to afford 0.74 g (96%) of5-dimethylamino-1-methyl-3-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-oneas a white/pink solid. ¹H NMR (400 MHz, CDCl₃): 6.95 (d, J=8.3 Hz, 1H),6.08 (d, J=8.3 Hz, 1H), 4.35 (tt, J=12.1 Hz, 4.0 Hz, 1H), 3.25 (s, 3H),3.14 (d, J=12.4 Hz, 2H) 2.97 (s, 6H), 2.66 (td, J=12.9Hz, 1.3 Hz, 2H),2.53 (qd, J=12.4 Hz, 4.0 Hz, 2H), 1.69 (d, J=11.9 Hz, 2H).

E.(S)-5-Dimethylamino-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

To a stirring solution of 0.24 g (0.0009 mol) of5-dimethylamino-1-methyl-3-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-onein EtOH/Dichloroethane (1.5 mL/1.5 mL) was added 0.23 g (0.0005 mol) of(R)-5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine.The reaction mixture was heated to 80° C. and stirred for 16 h andconcentrated. The crude product was then dissolved in CH₂Cl₂ (40 mL) andpurified using flash chromatography (0-6% MeOH/CH₂Cl₂) affording 0.38 g(97%) of the desired product as a white solid. MS (electrospray): exactmass calculated for C₃₁H₃₉F₃N₈O₄S, 676.28; m/z found, 677.28 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃):7.71 and 7.67 (A and B of AA′BB′ quartet,J_(ab)=8.3 Hz, 4H), 7.03 (d, J=8.6 Hz, 1H), 6.16 (d, J=8.6 Hz, 1H), 4.58and 4.56 (A and B of AB quartet, J_(ab)=14.5 Hz, 2H), 4.36 (tt, J=12.1Hz, 4.04 Hz, 1H), 4.25-4.01 (m, 4H), 3.77-3.60 (m, 2H), 3.33 (s, 3H),3.16-3.04 (m, 2H), 3.03 (s, 6H), 2.99-2.90 (m, 2H), 2.88 (s, 3H), 2.77(qd, J=12.1 Hz, 3.54 Hz, 2H), 2.56-2.42 (m, 3H), 2.21 (t, J=11.6 Hz,1H), 1.75 (d, J=11.6 Hz, 2H).

Example 32

1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-oneExample 33

1-(1-{3-[3-(3,4-Dichloro-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-oneExample 34

3-(3,4-Dichloro-phenyl)-1-{3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid amide Example 35

6-Chloro-1-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-oneExample 36

3-(3,4-Dichloro-phenyl)-1-{3-[4-(3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid amide Example 37

[3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-acetonitrileExample 38

[3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-aceticacid ethyl ester Example 39

5-Chloro-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-dihydro-benzoimidazol-2-oneExample 40

1-{3-[4-(6-Chloro-3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3-(3,4-dichloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid amide Example 41

3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,5-dimethyl-1,3-dihydro-benzoimidazol-2-oneExample 42

3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-oneExample 43

3-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-methoxy-1,3-dihydro-imidazo[4,5-b]pyridin-2-oneExample 44

3-(4-Bromo-phenyl)-1-{2-hydroxy-3-[4-(5-methoxy-2-oxo-1,2-dihydro-imidazo[4,5-b]pyridin-3-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid amide Example 45

3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-methoxy-1-methyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-oneExample 46

5-Dimethylamino-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-oneExample 47

6-Chloro-1-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-oneExample 48

1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-oneExample 49

4-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-benzo[1,4]oxazin-3-oneExample 50

4-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-benzo[1,4]oxazin-3-oneExample 51

1-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinazolin-2-oneExample 52

Cathepsin S Inhibition Assay.

Recombinant human cathepsin S (CatS) was expressed in the baculovirussystem and purified in one step with a thiopropyl-sepharose column. 10-Lyielded ˜700 mg of CatS and N-terminal sequencing confirmed identity.The assay is run in 100 mM sodium acetate pH 5.0 containing 1 mM DTT and100 mM NaCl. The substrate for the assay is

-   -   (Aedens)EKARVLAEAA(Dabcyl)K-amide

The K_(m) for the substrate is around 5 μM but the presence of substrateinhibition makes kinetic analysis difficult. With 20 μM substrate theassay rate is linear over the range of 1-8 ng CatS in 100 μl reaction.Using 2 ng/well of CatS, the production of product is linear and yields˜7-fold signal after 20 min with only 20% loss of substrate. Primaryassays are run by quenching the reaction after 20 min with 0.1% SDS andthen measuring the fluorescence. For other assays, measurements aretaken every min for 20 min. The rate is calculated from the slope of theincrease and the percent inhibition is calculated from this (See Tables1 and 2 below). TABLE 1 EXAMPLE IC₅₀ (μM) 1 0.73 2 0.07 3 0.28 4 0.19 51.16 6 0.19 7 0.26 8 0.04 9 0.10 10 0.09 11 0.03 12 0.62 13 0.37 14 0.2915 0.23 16 0.30 17 1.30 18 0.25 19 0.02 20 0.01 21 0.02 22 0.03 23 0.0824 0.03 25 0.23 26 0.18 27 0.09 28 0.89 29 0.78 30 0.04 31 0.07

TABLE 2 EXAMPLE IC₅₀ (μM) 32 0.06 33 0.01 34 0.02 35 0.03 36 0.04 370.05 38 0.02 39 0.04 40 0.04 41 0.03 42 0.08 43 0.02 44 0.03 45 0.02 460.03 47 0.04 48 0.02 49 0.02 50 0.02 51 0.02

Example 1011-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-octahydro-benzoimidazol-2-oneExample 1021-(1-{3-[5-Acetyl-3-(3,4-dichloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl-piperidin-4-yl)-octahydro-benzoimidazol-2-oneExample 103 Acetic acid1-(1-{3-[5-acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1H-benzoimidazol-2-ylester Example 104 Methanesulfonic acid1-(1-{3-[3-(4-bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1H-benzoimidazol-2-ylester Example 1051-(1-{3-[5-Acetyl-3-(3,4-dichloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-chloro-1,3-dihydro-indol-2-oneExample 1061-{3-[4-(5-Chloro-2-oxo-2,3-dihydro-indol-1-yl)-piperidin-1-yl]-propyl}-3-(3,4-dichloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid amide Example 1071-{3-[4-(5-Chloro-2-oxo-2,3-dihydro-indol-1-yl)-piperidin-1-yl]-propyl}-3-(3,4-dichloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid methylamide Example 108 Acetic acid1-(1-{3-[5-acetyl-3-(3,4-dichloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1H-benzoimidazol-2-ylester Example 109 Methanesulfonic acid1-(1-{3-[3-(3,4-dichloro-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1H-benzoimidazol-2-ylester Example 1101-[1-{3-[4-(3,5-Dichloro-pyridin-4-ylamino)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 1111-[1-{3-[4-(Benzooxazol-2-yloxy)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 1121-[1-{3-[4-(Benzooxazol-2-ylamino)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 1131-(4-Benzooxazol-2-yl-piperidin-1-yl)-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-olExample 1141-(4-Benzothiazol-2-yl-piperidin-1-yl)-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-olExample 1151-{3-[4-(5-Methyl-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid amide Example 116N-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-N-(3-chloro-phenyl)-benzamideExample 1174-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-methyl-4H-benzo[1,4]oxazin-3-oneExample 1184-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-methyl-4H-benzo[1,4]oxazin-3-oneExample 1193-(4-Bromo-phenyl)-1-{3-[4-(5-methyl-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid amide Example 1204-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-methyl-4H-benzo[1,4]oxazin-3-oneExample 1214-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-methyl-4H-benzo[1,4]oxazin-3-oneExample 1223-(4-Bromo-phenyl)-1-{3-[4-(6-ethanesulfonyl-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid amide Example 1234-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-6-ethanesulfonyl-4H-benzo[1,4]oxazin-3-oneExample 1244-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-6-ethanesulfonyl-4H-benzo[1,4]oxazin-3-oneExample 1251-[1-[3-(4-Benzothiazol-2-yl-piperidin-1-yl)-2-hydroxy-propyl]-3-(4-chloro-3-methyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 1261-[1-[3-(4-Benzothiazol-2-yl-piperidin-1-yl)-2-hydroxy-propyl]-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 1271-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-3,4-dihydro-1H-quinolin-2-oneExample 1281-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-3,4-dihydro-1H-quinolin-2-oneExample 1291-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-3,4-dihydro-1H-quinolin-2-oneExample 1301-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-3,4-dihydro-1H-quinazolin-2-oneExample 1311-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-3,4-dihydro-1H-quinazolin-2-oneExample 1321-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(6-chloro-2,2-dioxo-3,4-dihydro-2H-2λ⁶-2,1,3-benzothiadiazin-1-yl)-piperidin-1-yl]-propan-2-olExample 1331-[4-(6-Chloro-2,2-dioxo-2,3-dihydro-2λ⁶-2,1,3-benzothiadiazol-1-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-olExample 1341-[1-{3-[4-(6-Chloro-2,2-dioxo-2,3-dihydro-2λ⁶-2,1,3-benzothiadiazol-1-yl)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 1354-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-4-1,4-benzoxazin-3-oneExample 1361-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-oneExample 1371-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-oneExample 1384-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-4H-1,4-benzoxazin-3-oneExample 1394-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-4H-1,4-benzoxazin-3-oneExample 1401-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-oneExample 1411-{2-Hydroxy-3-[4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester Example 1421-{2-Hydroxy-3-[4-(3-oxo-2,3-dihydro-1,4-benzoxazin-4-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester Example 1434-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-4H-1,4-benzoxazin-3-oneExample 1444-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-1,4-benzoxazin-3-oneExample 1451-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-oneExample 1461-{3-[4-(2-Oxo-3,4-dihydro-2H-quinolin-1-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester Example 1471-{3-[4-(3-Oxo-2,3-dihydro-1,4-benzoxazin-4-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester Example 1486-Chloro-4-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-1,4-benzoxazin-3-oneExample 1494-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-6-chloro-4H-1,4-benzoxazin-3-oneExample 1504-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-1,4-benzoxazin-3-oneExample 1511-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-oneExample 1524-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-4H-1,4-benzoxazin-3-oneExample 1531-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-one Example 1541-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-oneExample 1551-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-oneExample 1561-(1-{3-[5-Acetyl-3-(3-chloro-4-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-oneExample 1571-(1-{3-[3-(4-Chloro-3-methyl-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-oneExample 1581-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-oneExample 1591(1-{3-[5-Acetyl-3-(4-nitro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-oneExample 1601-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-oneExample 1611-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihydro-indol-2-oneExample 1626-Chloro-1-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-oneExample 1631-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-chloro-1,3-dihydro-indol-2-oneExample 1645-Chloro-1-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-oneExample 1651-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-chloro-1,3-dihydro-indol-2-oneExample 1661-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-chloro-1,3-dihydro-indol-2-oneExample 1674-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-4H-pyrido[3,2-b]-1,4-oxazin-3-oneExample 1681-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,5-dihydro-4,1-benzoxazepin-2-oneExample 1691-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,4-dihydro-3,1-benzoxazin-2-oneExample 1701-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,4-dihydro-3,1-benzoxazin-2-oneExample 1711-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,5-dihydro-4,1-benzoxazepin-2-oneExample 1721-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,4-dihydro-3,1-benzoxazin-2-oneExample 1731-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,4-dihydro-3,1-benzoxazin-2-oneExample 1741-(3-(4-Chloro-3-methyl-phenyl)-1-{2-hydroxy-3-[4-(5-nitro-2,3-dihydro-indol-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1751-(3-(4-Chloro-3-methyl-phenyl)-1-{2-hydroxy-3-[4-(6-nitro-2,3-dihydro-indol-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1761-(3-(4-Chloro-3-methyl-phenyl)-1-{2-hydroxy-3-[4-(2-methyl-2,3-dihydro-indol-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1771-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H>-quinazolin-2-oneExample 1781-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinazolin-2-oneExample 1791-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinazolin-2-oneExample 1801-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinazolin-2-oneExample 1811-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinazolin-2-one Example 1821-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1-(3-chloro-phenyl)-3-methyl-ureaExample 1831-[3-(4-Benzotriazol-1-yl-piperidin-1-yl)-2-hydroxy-propyl]-3-(3,4-dichloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester Example 1841-{3-[4-(5-Chloro-2-oxo-2,3-dihydro-indol-1-yl)-piperidin-1-yl]-propyl}-3-(3,4-dichloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester Example 1855-Chloro-1-(1-{3-[3-(3,4-dichloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-oneExample 1861-{3-[4-(5-Methyl-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester Example 1873-(4-Bromo-phenyl)-1-{3-[4-(5-methyl-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester Example 1883-(4-Bromo-phenyl)-1-{3-[4-(6-ethanesulfonyl-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester Example 1871-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(5-trifluoromethyl-benzothiazol-2-yl)-piperidin-1-yl]-propan-2-olExample 1905-Methyl-4-(1-{3-[3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-benzo[1,4]oxazin-3-oneExample 1914-(1-{3-[3-(4-Bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-methyl-4H-benzo[1,4]oxazin-3-oneExample 1924-(1-{3-[3-(4-Bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-6-ethanesulfonyl-4H-benzo[1,4]oxazin-3-oneExample 1931-{3-[4-(6-Chloro-indol-1-yl)-piperidin-1-yl]-propyl}-5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridineExample 1943-(4-Bromo-phenyl)-1-{3-[4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester Example 1953-(4-Bromo-phenyl)-1-{2-hydroxy-3-[4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester Example 1963-(4-Bromo-phenyl)-1-{2-hydroxy-3-[4-(3-oxo-2,3-dihydro-1,4-benzoxazin-4-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester Example 1971-(1-{3-[3-(4-Trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-oneExample 1983-(4-Bromo-phenyl)-1-{3-[4-(3-oxo-2,3-dihydro-1,4-benzoxazin-4-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester Example 1991-(1-{2-Hydroxy-3-[3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-oneExample 2004-(1-{3-[3-(4-Trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-1,4-benzoxazin-3-oneExample 2011-(1-{3-[3-(4-Bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-oneExample 2024-(1-{3-[3-(4-Bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-1,4-benzoxazin-3-oneExample 2031-(1-{3-[3-(4-Bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-oneExample 2044-(1-{3-[3-(4-Bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-4H-1,4-benzoxazin-3-oneExample 2054-(1-{2-Hydroxy-3-[3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-1,4-benzoxazin-3-oneExample 2061-(3-(3,4-Difluoro-phenyl)-1-{3-[4-(2,3-dihydro-indol-1-yl)-piperidin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 2071-[1-{3-[4-(5-Bromo-2,3-dihydro-indol-1-yl)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-chloro-3-methyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 2081-(1-{3-[5-Acetyl-3-(3,4-difluoro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-oneExample 2091-[1-{3-[4-(5-Bromo-2,3-dihydro-indol-1-yl)-piperidin-1-yl]-2-hydroxy-propyl}-3-(3,4-difluoro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 2101-(1-{3-[3-(4-Bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinazolin-2-oneExample 2111-(1-{3-[3-(4-Trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinazolin-2-oneExample 2121-(1-{3-[3-(4-Bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinazolin-2-oneExample 2131-(3-(4-Chloro-phenyl)-1-{3-[4-(3-chloro-phenylamino)-piperidin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 214N-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-N-(3-chloro-phenyl)-acetamideExample 2151-(4-Benzoimidazol-1-yl-piperidin-1-yl)-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-olExample 2161-(3-(4-Chloro-phenyl)-1-{2-hydroxy-3-[4-(2-methoxy-phenylamino)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 2171-(3-(4-Chloro-phenyl)-1-{3-[4-(2-fluoro-phenylamino)-piperidin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 2181-{3-(4-Chloro-phenyl)-1-[2-hydroxy-3-(4-phenylamino-piperidin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanoneExample 2191-(3-(4-Chloro-phenyl)-1-{3-[4-(4-chloro-phenylamino)-piperidin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 2201-[1-{3-[4-(4-Bromo-phenylamino)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-chloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 2214-(1-{3-[5-Acetyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-ylamino)-benzonitrileExample 2221-{3-(4-Chloro-phenyl)-1-[2-hydroxy-3-(4-p-tolylamino-piperidin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanoneExample 2231-(3-(4-Chloro-phenyl)-1-{2-hydroxy-3-[4-(4-methoxy-phenylamino)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 2241-(3-(4-Chloro-phenyl)-1-{2-hydroxy-3-[4-(3-methoxy-phenylamino)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 2251-(3-(4-Chloro-phenyl)-1-{3-[4-(3,5-dimethoxy-phenylamino)-piperidin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 2261-[1-{3-[4-(5-Chloro-2-methyl-phenylamino)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-chloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 2271-(3-(4-Chloro-phenyl)-1-{3-[4-(3-chloro-phenylamino)-piperidin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 228[2-(1-{3-[3-(4-Bromo-phenyl)-5-carbamoyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-ylamino)-4-ethanesulfonyl-phenoxy]-aceticacid methyl ester Example 229[2-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-ylamino)-4-ethanesulfonyl-phenoxy]-aceticacid methyl ester Example 230[2-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-ylamino)-4-ethanesulfonyl-phenoxy]-aceticacid methyl ester Example 2313-(4-Bromo-phenyl)-1-{3-[4-(5-ethanesulfonyl-2-methoxycarbonylmethoxy-phenylamino)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester Example 232[2-(1-{3-[3-(4-Bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-ylamino)-4-ethanesulfonyl-phenoxy]-aceticacid methyl ester Example 2331-{3-(4-Bromo-phenyl)-1-[2-hydroxy-3-(4-o-tolyloxy-piperidin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanoneExample 2341-{3-(4-Bromo-phenyl)-1-[2-hydroxy-3-(4-phenoxy-piperidin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanoneExample 2351-{3-(4-Bromo-phenyl)-1-[2-hydroxy-3-(4-p-tolyloxy-piperidin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanoneExample 2361-(3-(4-Bromo-phenyl)-1-{2-hydroxy-3-[4-(4-methoxy-phenoxy)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 2371-(3-(4-Bromo-phenyl)-1-{3-[4-(4-chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 2381-(3-(4-Bromo-phenyl)-1-{3-[4-(3-chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 2391-(3-(4-Bromo-phenyl)-1-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 2401-{3-(4-Chloro-3-methyl-phenyl)-1-[2-hydroxy-3-(4-phenoxy-piperidin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanoneExample 2411-{3-(4-Chloro-3-methyl-phenyl)-1-[2-hydroxy-3-(4-p-tolyloxy-piperidin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanoneExample 2421-(3-(4-Chloro-3-methyl-phenyl)-1-{2-hydroxy-3-[4-(4-methoxy-phenoxy)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 2431-(3-(4-Chloro-3-methyl-phenyl)-1-{3-[4-(4-chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 2441-(3-(4-Chloro-3-methyl-phenyl)-1-{3-[4-(3-chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 2451-{3-(4-Chloro-3-methyl-phenyl)-1-[2-hydroxy-3-(4-o-tolyloxy-piperidin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanoneExample 2451-(3-(4-Chloro-3-methyl-phenyl)-1-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 2462-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yloxy)-benzonitrileExample 2472-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yloxy)-benzonitrileExample 2481-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(4-chloro-phenoxy)-piperidin-1-yl]-propan-2-olExample 2491-[1-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 2501-(1-{3-[5-Acetyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-oneExample 2511-{1-[3-(5-Acetyl-3-phenyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl)-2-hydroxy-propyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-oneExample 2521-(1-{3-[5-Acetyl-3-(4-trifluoromethoxy-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-oneExample 2531-(1-{3-[5-Acetyl-3-(4-iodo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-oneExample 2541-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-oneExample 2551-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-oneExample 2561-(1-{3-[5-Acetyl-3-(4-chloro-3-nitro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-oneExample 2571-(1-{3-[5-Acetyl-3-(4-trifluoromethylsulfanyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-oneExample 2581-(1-{3-[5-Acetyl-3-(4-methanesulfonyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-oneExample 2591-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihydro-benzoimidazol-2-oneExample 2601-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-oneExample 2611-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-ethyl-1,3-dihydro-benzoimidazol-2-oneExample 2621-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-isopropyl-1,3-dihydro-benzoimidazol-2-oneExample 2631-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-butyl-1,3-dihydro-benzoimidazol-2-oneExample 2641-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-benzyl-1,3-dihydro-benzoimidazol-2-oneExample 2651-(1-{3-[5-Acetyl-3-(4-iodo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-fluoro-1,3-dihydro-benzoimidazol-2-oneExample 2663-(1-3-[5-Acetyl-3-(4-iodo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-7-fluoro-2-oxo-2,3-dihydro-1H-benzoimidazole-4-carbonitrileExample 2671-(1-{3-[5-Acetyl-3-(4-iodo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-fluoro-1,3-dihydro-benzoimidazol-2-oneExample 2683-(1-{3-[5-Acetyl-3-(4-iodo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carbonitrileExample 2691-{2-Hydroxy-3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid amide Example 2701-(1-{3-[3-(4-Chloro-3-methyl-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-oneExample 2713-(4-Chloro-3-methyl-phenyl)-1-{2-hydroxy-3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid methylamide Example 2723-(4-Chloro-3-methyl-phenyl)-1-{2-hydroxy-3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid ethylamide Example 2731-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-methyl-1,3-dihydro-benzoimidazol-2-oneExample 2741-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-methyl-1,3-dihydro-benzoimidazol-2-oneExample 2751-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5,6-dichloro-1,3-dihydro-benzoimidazol-2-oneExample 2761-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-methyl-1,3-dihydro-benzoimidazol-2-oneExample 2771-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-methyl-1,3-dihydro-benzoimidazol-2-oneExample 2781-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5,6-dichloro-1,3-dihydro-benzoimidazol-2-oneExample 2791-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihydro-benzoimidazol-2-oneExample 2801-(1-{3-[5-Acetyl-3-(4-chloro-3-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-oneExample 2811-(1-{3-[3-(4-Chloro-3-methyl-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2-morpholin-4-yl-ethyl)-1,3-dihydro-benzoimidazol-2-oneExample 2821-(1-{3-[5-Acetyl-3-(3-fluoro-4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-oneExample 2831-(1-{3-[5-Acetyl-3-(4-bromo-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-oneExample 284(R)-1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-oneExample 2851-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-methoxy-1,3-dihydro-benzoimidazol-2-oneExample 2861-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-7-chloro-1,3,-dihydro-benzoimidazol-2-oneExample 2873-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-oneExample 2881-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-7-methyl-1,3-dihydro-benzoimidazol-2-oneExample 289(R)-1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihydro-benzoimidazol-2-oneExample 2901-(1-{3-[5-Acetyl-3-(3,4-dichloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-oneExample 2911-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-oneExample 2921-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihydro-benzoimidazol-2-oneExample 293(S)-1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihydro-benzoimidazol-2-oneExample 294(R)-1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-oneExample 295(R)-1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihydro-benzoimidazol-2-oneExample 2962-{2-[3-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-ethyl}-isoindole-1,3-dioneExample 2971-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2-amino-ethyl)-1,3-dihydro-benzoimidazol-2-oneExample 2981-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-oneExample 2991-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-ethyl-1,3-dihydro-benzoimidazol-2-oneExample 3001-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-oneExample 3011-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-ethyl-1,3-dihydro-benzoimidazol-2-oneExample 3026-Chloro-1-(1-{3-[3-(4-chloro-3-methyl-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-oneExample 3031-(1-{3-[5-Acetyl-3-(3-chloro-4-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-oneExample 3043-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-chloro-1-(2-morpholin-4-yl-ethyl)-1,3-dihydrobenzoimidazol-2-oneExample 305[3-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-aceticacidethyl ester Example 3061-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2,2,2-trifluoro-ethyl)-1,3-dihydrobenzoimidazol-2-oneExample 307[3-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]acetonitrileExample 3081-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2-hydroxy-ethyl)-1,3-dihydro-benzoimidazol-2-oneExample 3091-(1-{3-[5-Acetyl-3-(3-chloro-4-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihydro-benzoimidazol-2-oneExample 3101-(1-{3-[5-Acetyl-3-(3-chloro-4-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-oneExample 3111-Ethyl-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-oneExample 3121-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-oneExample 3131-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2-hydroxy-ethyl)-1,3-dihydro-benzoimidazol-2-oneExample 3143-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-oneExample 315[3-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-acetonitrileExample 3162-[3-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-acetamideExample 3171-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl)-piperidin-4-yl)-3-(2-oxo-tetrahydro-furan-3-yl)-1,3-dihydro-benzoimidazol-2-oneExample 3181-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2-methoxy-ethyl)-1,3-dihydro-benzoimidazol-2-oneExample 3191-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2-oxo-butyl)-1,3-dihydro-benzoimidazol-2-oneExample 3201-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2-diethylamino-ethyl)-1,3-dihydro-benzoimidazol-2-oneExample 3211-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-cyclopropylmethyl-1,3-dihydro-benzoimidazol-2-oneExample 3221-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2-methyl-allyl)-1,3-dihydro-benzoimidazol-2-oneExample 3231-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-methyl-1,3-dihydro-benzoimidazol-2-oneExample 3245-Chloro-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-dihydro-benzoimidazol-2-oneExample 3256-Chloro-1-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-oneExample 326N-[4-(5-Acetyl-1-{2-hydroxy-3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-phenyl]-acetamideExample 327[3-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-aceticacid Example 3281-(1-{3-[5-Acetyl-3-(3-bromo-4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-oneExample 3293-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-oneExample 3303-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-oneExample 331 1-(1-{3-[5-(1H-Imidazole-4-carbonyl)-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-oneExample 3321-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid amide Example 3331-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid ethylamide Example 3341-(1-{3-[5-(Isoxazole-5-carbonyl)-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-oneExample 3351-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-sulfonicacid (N-t-butoxycarbonyl)amide Example 3361-Methyl-3-(1-{3-[5-(5-methyl-isoxazole-3-carbonyl)-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-oneExample 3373-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-methoxy-1-methyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-oneExample 3383-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-methoxy-1-methyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-oneExample 3395-Dimethylamino-3-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-oneExample 3403-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-ethyl-5-methoxy-1,3-dihydro-imidazo[4,5-b]pyridin-2-oneExample 3411-(1-{3-[5-Acetyl-3-(4-nitro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-oneExample 3421-(1-{3-[5-Acetyl-3-(4-nitro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-oneExample 3433-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-ethyl-5-methoxy-1,3-dihydro-imidazo[4,5-b]pyridin-2-oneExample,3443-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-methoxy-1-methyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-oneExample 3451-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid benzyl ester Example 3465-Dimethylamino-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-oneExample 3471-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carbothioicacid methylamide Example 3483-(4-Bromo-phenyl)-1-{3-[4-(3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid phenylamide Example 3491-(1-{3-[5-Benzoyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-oneExample 3501-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-oneExample 3511-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-oneExample 3523-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-chloro-1-methyl-1,3-dihydro-benzoimidazol-2-oneExample 3531-{3-[4-(6-Chloro-3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid amide Example 3541-(1-{3-[3-(4-Bromo-phenyl)-5-phenylmethanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-oneExample 3551-(1-{3-[5-Acetyl-3-(3,4-dichloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-oneExample 3563-(4-Bromo-phenyl)-1-{3-[4-(3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid amide Example 3573-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-chloro-1-methyl-1,3-dihydro-benzoimidazol-2-oneExample 3583-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-chloro-1-methyl-1,3-dihydro-benzoimidazol-2-oneExample 3593-(4-Bromo-phenyl)-1-{3-[4-(6-chloro-3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid amide Example 3603-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,5-dimethyl-1,3-dihydro-benzoimidazol-2-oneExample 3611-(1-{3-(5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-oneExample 3623-(4-Bromo-phenyl)-1-{3-[4-(3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-sulfonicacid t-butoxycarbonyl-amide Example 3631-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-oneExample 3641-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-oneExample 3653-(4-Bromo-phenyl)-1-{3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-sulfonicacid t-butoxycarbonyl-amide Example 3663-(4-Bromo-phenyl)-1-{3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid amide Example 367(R)-5-Chloro-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-dihydro-benzoimidazol-2-oneExample 3681-(1-{3-[5-Acetyl-3-(3,4-dichloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-oneExample 3691-(1-{3-[3-(3,4-Dichloro-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-oneExample 3701-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-methoxy-1,3-dihydro-benzoimidazol-2-oneExample 3713-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-oneExample 3723-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-methoxy-1,3-dihydro-imidazo[4,5-b]pyridin-2-oneExample 3731-{2-Hydroxy-3-[4-(2-oxo-1,2-dihydro-imidazo[4,5-b]pyridin-3-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid amide Example 3743-(4-Bromo-phenyl)-1-{2-hydroxy-3-[4-(2-oxo-1,2-dihydro-imidazo[4,5-b]pyridin-3-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid amide Example 375[3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl]-acetonitrileExample 3763-(3,4-Dichloro-phenyl)-1-{3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid methylamide Example 3773-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-oneExample 3783-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-methoxy-1,3-dihydro-imidazo[4,5-b]pyridin-2-oneExample 379[3-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-aceticacid ethyl ester Example 380[3-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-aceticacid ethyl ester Example 381[3-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl]-piperidin-4-yl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-aceticacid ethyl ester Example 3825-Chloro-3-(1-{3-[3-(3,4-dichloro-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-dihydro-benzoimidazol-2-oneExample 383(R)-1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-oneExample 3841-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-pyridin-4-ylmethyl-1,3-dihydro-benzoimidazol-2-oneExample 385(R)-5-Dimethylamino-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-oneExample 3863-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-chloro-3H-benzooxazol-2-oneExample 3873-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-4-methyl-3H-benzooxazol-2-oneExample 3883-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-benzooxazole-6-carboxylicacid ethyl ester Example 3893-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-ethanesulfonyl-3H-benzooxazol-2-oneExample 3903-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-4-methyl-3H-benzooxazol-2-oneExample 3913-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-benzooxazole-6-carboxylicacid ethyl ester Example 3923-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-methoxy-3H-benzooxazol-2-oneExample 3933-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-ethanesulfonyl-3H-benzooxazol-2-oneExample 3943-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-methoxy-3H-benzooxazol-2-oneExample 3953-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3H-benzooxazol-2-oneExample 3963-(1-3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-chloro-3H-benzooxazol-2-oneExample 3973-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3H-oxazolo[4,5-b]pyridin-2-oneExample 3981-[1-[3-(4-Benzooxazol-2-yl-piperidin-1-yl)-2-hydroxy-propyl]-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 3991-[1-{2-Hydroxy-3-[4-(6-methyl-benzooxazol-2-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 4001-[1-{3-[4-(Benzothiazol-2-yloxy)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 4011-[1-{2-Hydroxy-3-[4-(5-methyl-benzooxazol-2-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 4021-(3-(4-Chloro-phenyl)-1-{2-hydroxy-3-[4-(2-methoxy-phenyl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 4033-(4-Chloro-phenyl)-1-{2-hydroxy-3-[4-(2-methoxy-phenyl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carbaldehydeExample 4041-[1-[3-(4-Benzo[b]thiophen-2-yl-piperidin-1-yl)-2-hydroxy-propyl]-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 4051-[4-(6-Chloro-indol-1-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-olF. Other Embodiments

The features and advantages of the invention are apparent to one ofordinary skill in the art. Based on this disclosure, including thesummary, detailed description, background, examples, and claims, one ofordinary skill in the art will be able to make modifications andadaptations to various conditions and usages. These other embodimentsare also within the scope of the invention.

1. A compound of formula I:

wherein: Ar₂ is a monocyclic or bicyclic ring system, unsaturated,saturated or aromatic, optionally fused, optionally including between 1and 5 heteroatom ring moieties independently selected from O, S, N, SO₂,and C═O; said Ar₂ ring system being optionally substituted with between1 and 4 substituents; R⁵ and R⁶ are independently selected from hydrogenand C₁₋₅ alkyl; R⁷ is C₁₋₅ alkyl, C₂₋₅ alkenyl, C₁₋₅ alkoxy, C₁₋₅alkylthio, halogen, or a 4-7 membered carbocyclyl or heterocyclyl; R⁸ ishydrogen, C₁₋₅ alkyl, C₂₋₅ alkenyl, C₁₋₅ alkoxy, C₁₋₅ alkylthio,halogen, or a 4-7 membered carbocyclyl or heterocyclyl; alternatively,R⁷ and R⁸ can be taken together to form an optionally substituted 5- to7-membered carbocyclic or heterocyclic ring, which ring may beunsaturated or aromatic, and may be optionally substituted with betweenone and three substituents independently selected from halo, cyano,amino, hydroxy, nitro, R⁴, R⁴O—, R⁴S—, R⁴O(C₁₋₅ alkylene)-, R⁴O(C═O)—,R⁴(C═O)—, R⁴(C═S)—, R⁴(C═O)O—, R⁴O(C═O)(C═O)—, R⁴SO₂, NHR⁴⁴SO₂—, andNHR⁴⁴(C═O)—; R⁴ is H, C₁₋₅ alkyl, C₂₋₅ alkenyl, C₁₋₅ heterocyclyl, (C₁₋₅heterocyclyl)C₁₋₆ alkylene, phenyl, benzyl, phenethyl, NH₂, mono- ordi(C₁₋₆ alkyl)N—, or R⁴²OR⁴³—, wherein R⁴² is H, C₁₋₅ alkyl, C₂₋₅alkenyl, phenyl, benzyl, phenethyl, C₁₋₅ heterocyclyl, or (C₁₋₅heterocyclyl)C₁₋₆ alkylene and R⁴³ is C₁₋₅ alkylene, phenylene, ordivalent C₁₋₅ heterocyclyl; R⁴⁴ is any of the values for R⁴; n is 0, 1,or 2; G is C₃₋₆ alkenediyl or C₃₋₆ alkanediyl, optionally substitutedwith hydroxy, halogen, C₁₋₅ alkoxy, C₁₋₅ alkyl, oxo, hydroximino,CO₂R^(k), R^(k)R^(l)N, R^(k)R^(l)NCO₂, (L)-C₁₋₄ alkylene-, (L)-C₁₋₅alkoxy, N₃, or [(L)-C₁₋₅ alkylene]amino; each of R^(k) and R^(l) isindependently hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, benzyl,phenethyl, or C₁₋₅ heterocyclyl; alternatively R^(k) and R^(l), can betaken together to form an optionally substituted 4- to 7-memberedheterocyclic ring, which ring may be saturated, unsaturated or aromatic;L is amino, mono- or di-C₁₋₅ alkylamino, pyrrolidinyl, morpholinyl,piperidinyl homopiperidinyl, or piperazinyl, wherein available ringnitrogens may be optionally substituted with C₁₋₅ alkyl, benzyl, C₂₋₅acyl, C₁₋₅ alkylsulfonyl, or C₁₋₅ alkoxycarbonyl; Ar represents amonocyclic or bicyclic aryl or heteroaryl ring, optionally substitutedwith between 1 and 3 substituents independently selected from halogen,C₁₋₅alkoxy, C₁₋₅ alkyl, C₂₋₅ alkenyl, cyano, nitro, R²²R²³N, R²⁴SO₂,R²⁴S, R²⁴SO R²⁴OC═O, R²²R²³NC═O, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy, C₁₋₅haloalkylthio, and C₁₋₅ alkylthio; R²² is hydrogen, C₁₋₅ alkyl, C₃₋₅alkenyl, phenyl, phenethyl, benzyl, or C₁₋₅ heterocyclyl, C₂₋₈ acyl,aroyl, R³⁸OC═O R²⁵R²⁶NC═O, R³⁸SO, R³⁸SO₂, R³⁸S, or R²⁵R²⁶NSO₂; R³⁸ is H,C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, benzyl, phenethyl, or C₁₋₅heterocyclyl; R²³ is hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, benzylor C₁₋₅ heterocyclyl; alternatively, R²² and R²³ can be taken togetherto form an optionally substituted 4- to 7-membered heterocyclic ring,which ring may be saturated, unsaturated or aromatic; R²⁴ is C₁₋₅ alkyl,C₃₋₅ alkenyl, phenyl, benzyl, or C₁₋₅ heterocyclyl; R²⁵ and R²⁶independently are hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, benzyl, orC₁₋₅ heterocyclyl; or, alternatively, R²⁵ and R²⁶ can be taken togetherto form an optionally substituted 4- to 7-membered heterocyclic ring,which ring may be saturated, unsaturated or aromatic; W represents O, S,NR²⁷, C═O, (C═O)NH, NH(C═O), or CHR²⁸; R^(z) is H or OH and the dashedline is absent; or R^(z) is absent where the dashed line is an sp² bond;R²⁷ is hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, naphthyl, benzyl,phenethyl, C₁₋₅ heterocyclyl, C₂₋₈ acyl, aroyl, R²⁹OC═O, R³⁰R³¹NC═O,R²⁹SO, R²⁹S, R²⁹SO₂, or R³⁰R³¹NSO₂; or, alternatively, R²⁷ and part ofAr₂ can be taken together to form an optionally substituted 5- or6-membered heterocyclic ring with optionally 1 to 3 additionalheteroatom moieties in the ring selected from O, NR⁹, NR¹⁰, N, SO₂, C═O,and S; which ring may be saturated, unsaturated or aromatic; R⁹and R¹⁰are independently selected from H, C₁₋₃ alkyl, and —CH₂CO₂(C₁₋₄ alkyl);R²⁸ is hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl, hydroxy, phenyl, benzyl, C₁₋₅heterocyclyl, R²⁹O, R³⁰R³¹NC═O, R²⁹S, R²⁹SO, R²⁹SO₂, or R³⁰R³¹NSO₂; R²⁹is C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, benzyl, or C₁₋₅ heterocyclyl; R³⁰and R³¹ are independently selected from hydrogen, C₁₋₅ alkyl, C₃₋₅alkenyl, phenyl, benzyl, phenethyl, naphthyl, and C₁₋₅ heteroaryl;alternatively, R³⁰ and R³¹ can be taken together to form an optionallysubstituted 4- to 7-membered ring carbocyclic or heterocyclic ring,which ring may be saturated, unsaturated or aromatic; wherein each ofthe above hydrocarbyl or heterocarbyl groups, unless otherwiseindicated, and in addition to any specified substituents, is optionallyand independently substituted with between 1 and 3 substituents selectedfrom methyl, halomethyl, hydroxymethyl, halo, hydroxy, amino, nitro,cyano, C₁₋₅ alkyl, C₁₋₅ alkoxy, —COOH, C₂₋₆ acyl, [di(C₁₋₄alkyl)amino]C₂₋₅ alkylene, [di(C₁₋₄ alkyl)amino]C₂₋₅ alkyl-NH—CO—, andC₁₋₅ haloalkoxy; or a pharmaceutically acceptable salt, amide, or esterthereof; or a stereoisomeric form thereof.
 2. A compound of claim 1,wherein Ar₂ is selected from 5-7 membered monocyclic rings, and [5,6],[6,6], [6,5], and [5,5] fused bicyclic ring systems, said ring or ringsystem being carbocyclic or heterocyclic, saturated, unsaturated, oraromatic, optionally substituted with halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ hydroxyalkyl, nitro, hydroxy, amino, mono- or di-(C₁₋₆ alkyl)amino,C₁₋₄ alkoxy, C₂₋₄ alkoxycarbonyl, C₂₋₆ acyl, C₂₋₆ acyloxy, C₁₋₅alkylsulfonyl, C₁₋₅ alkoxycarbonylC₁₋₄ alkoxy, cyano, and mono- ordi-(C₁₋₆ alkyl)carbamoyl.
 3. A compound of claim 1, wherein Ar₂ isselected from 2,5-di(C₁₋₆ alkyl)aminopyrrolyl and the following 6formulae:

wherein each dashed line may be an sp² bond or absent; X_(c) is O, S, orN; and X_(d) is O or S; R¹ is hydrogen, halogen, C₁₋₅ alkoxy, hydroxy,C₁₋₅ alkyl, C₂₋₅ alkenyl, cyano, nitro, R^(a)R^(b)N, C₂₋₈ acyl, C₁₋₅heterocyclyl, (C₁₋₅ heterocyclyl)C₁₋₅ alkylene, R¹¹S, R¹¹SO, R¹¹SO₂,R^(c)OC═O, R^(c)R^(d)NC═O, or R^(c)R^(d)NSO₂; or R¹ can be takentogether with R²⁷ as provided below; R² is hydrogen, halogen, C₁₋₅alkoxy, hydroxy, C₁₋₅ alkyl, C₂₋₅ alkenyl, cyano, nitro, R^(e)R^(f)N,C₁₋₅ heterocyclyl, or C₂₋₈ acyl; R³ is hydrogen, halogen, C₁₋₅ alkoxy,hydroxy, C₁₋₅ alkyl, C₂₋₅ alkenyl, cyano, nitro, R^(g)R^(h)N, C₂₋₈ acyl,C₁₋₅ heterocyclyl, R^(h)OC═O, R^(g)R^(h)NC═O, or R^(g)R^(h)NS₂; R^(a) isselected from hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, benzyl,phenethyl, C₁₋₅ heterocyclyl, C₂₋₈ acyl, aroyl, R^(j)OC═O,R^(i)R^(j)NC═O, R¹²SO, R¹²SO₂, R¹²S, and R^(i)R^(j)NSO₂; R^(e) isselected from hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, benzyl,phenethyl, C₁₋₅ heterocyclyl, C₂₋₈ acyl, aroyl, R³²OC═O, R³²R³³NC═O,R¹³SO, R¹³SO₂, R¹³S, and R³²R³³NSO₂; R^(m) is selected from hydrogen,C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, benzyl, phenethyl, C₁₋₅ heterocyclyl,C₂₋₈ acyl, aroyl, R³⁴OC═O, R³⁴R³⁵NC═O, R¹⁵SO, R¹⁵SO₂, R¹⁵S, andR³⁴R³⁵NSO₂; R^(o) is selected from hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl,phenyl, benzyl, phenethyl, C₁₋₅ heterocyclyl, C₂₋₈ acyl, aroyl, R³⁶OC═O,R³⁶R³⁷NC═O, R¹⁹SO, R¹⁹SO₂, R¹⁹S, and R³⁶R³⁷NSO₂; each of R^(b), R^(f),R^(n), R^(p), R³², R³³, R³⁴, R³⁵, R³⁶, R³⁷, R³⁹, and R⁴⁰ isindependently selected from hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl,benzyl, phenethyl, and C₁₋₅ heteroaryl; alternatively, R^(a) and R^(b),R^(e) and R^(f), R^(m) and R^(n), and R^(o) and R^(p), independently,can be taken together to form an optionally substituted 4- to 7-memberedheterocyclic ring, which ring may be saturated, unsaturated or aromatic;each of R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁹, R³⁸, and R⁴¹ is independentlyC₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, benzyl, phenethyl, or C₁₋₅heterocyclyl; each of R^(c) and R^(d), and R^(i) and R^(j) areindependently are hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, benzyl,phenethyl, or C₁₋₅ heteroaryl; alternatively, R^(c) and R^(d), and R^(i)and R^(j), independently, can be taken together to form an optionallysubstituted 4- to 7-membered heterocyclic ring, which ring may besaturated, unsaturated or aromatic; R⁹ is hydrogen, C₁₋₅ alkyl, C₃₋₅alkenyl, phenyl, benzyl, phenethyl, or C₁₋₅ heterocyclyl, C₂₋₈ acyl,aroyl, R¹⁷OC═O, R¹⁷R¹⁸NC═O, R¹⁶S, R¹⁶SO, R¹⁶SO₂, or R¹⁷R¹⁸NSO₂; R^(h) ishydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, benzyl, phenethyl or C₁₋₅heterocyclyl; alternatively, R^(g) and R^(h) can be taken together toform an optionally substituted 4- to 7-membered heterocyclic ring, whichring may be saturated, unsaturated or aromatic; R¹⁷ and R¹⁸independently are hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, benzyl, orC₁₋₅ heterocyclyl; alternatively, R¹⁷ and R¹⁸ can be taken together toform an optionally substituted 4- to 7-membered heterocyclic ring, whichring may be saturated, unsaturated or aromatic; Y_(e) is nitrogen orR²⁰C; Z_(e) is nitrogen or R²¹C; R²⁰ is hydrogen, halogen, C₁₋₅ alkoxy,C₁₋₅ alkyl, C₂₋₅ alkenyl, cyano, nitro, R^(m)R^(n)N, C₂₋₈ acyl,R^(m)OC═O, R¹⁴S, R¹⁴SO, or R¹⁴SO₂; R²¹ is hydrogen, halogen, C₁₋₅alkoxy, C₁₋₅ alkyl, C₂₋₅ alkenyl, cyano, nitro, R^(o)R^(p)N, C₂₋₈ acyl,R¹⁶OC═O, R¹¹S, R¹¹SO, or R¹¹SO₂; alternatively, R³ and R²⁰ or R³ and R²¹can be taken together to form an optionally substituted 5- or 6-memberedcarbocyclic or heterocyclic ring, which ring may be saturated,unsaturated or aromatic; wherein said ring may be optionally substitutedwith halo, di(C₁₋₅ alkyl)amino, C₂₋₅ acyl, and C₁₋₅ alkoxy; R²⁷ ishydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, naphthyl, benzyl, phenethyl,C₁₋₅ heterocyclyl, C₂₋₈ acyl, aroyl, R²⁹OC═O, R³⁰R³¹NC═O, R²⁹SO, R²⁹S,R²⁹SO₂, or R³⁰R³¹NSO₂; or, alternatively, R²⁷ and R¹ can be takentogether to form an optionally substituted 5- or 6-membered heterocyclicring with optionally 1 to 3 additional heteroatom moieties in the ringselected from O, NR⁹, NR¹⁰, N, SO₂, C═O, and S; which ring may besaturated, unsaturated or aromatic; R⁹and R¹⁰ are independently selectedfrom H, C₁₋₃ alkyl, and —CH₂CO₂(C₁₋₄ alkyl); X_(f) is CHR^(1f), ═N—, NH,C═O, SO₂, CHSR^(1f) wherein, in formula (f), R^(1f) is hydrogen,halogen, C₁₋₅ alkoxy, hydroxy, C₁₋₅ alkyl, C₃₋₅ alkenyl, cyano, nitro,R³⁹R⁴⁰N, C₂₋₈ acyl, C₁₋₅ heterocyclyl, (C₁₋₅ heterocyclyl)C₁₋₅ alkylene,R⁴¹S, R⁴¹SO, R⁴¹SO₂, R³⁹OC═O, R³⁹R⁴⁰NC═O, R³⁹R⁴⁰NSO₂, R⁴¹SO₃— orR³⁹(C═O)O—; Y_(f) is CH₂, CHR^(2f), ═CR^(2f), O, or NR^(2f), whereinR^(2f) is H, C₁₋₅ alkyl, C₃₋₅ alkenyl, C₂₋₈ acyl, C₁₋₅ heterocyclyl,(C₁₋₅ heterocyclyl)-C₁₋₅ alkylene, C₁₋₅ haloalkyl, C₁₋₅ cyanoalkyl,(C₁₋₅ alkoxycarbonyl)C₁₋₅ alkylene, and (phenylcarbonyl)NH—; m is 0 or1;p is 0 or1; wherein each of the above hydrocarbyl or heterocarbylgroups, unless otherwise indicated, and in addition to any specifiedsubstituents, is optionally and independently substituted with between 1and 3 substituents selected from methyl, halomethyl, hydroxymethyl,halo, hydroxy, amino, nitro, cyano, C₁₋₅ alkyl, C₁₋₅ alkoxy, —COOH, C₂₋₆acyl, [di(C₁₋₄ alkyl)amino]C₂₋₅ alkylene, [di(C₁₋₄ alkyl)amino]C₂₋₅alkyl-NH—CO—, and C₁₋₅ haloalkoxy.
 4. A compound of claim 3, wherein Ar₂is selected from formulae (e).
 5. A compound of claim 3, wherein Ar₂ isselected from formulae (f).
 6. A compound of claim 3, wherein Ar₂ isselected from formula (a)-(d).
 7. A compound of claim 3, wherein R¹ ishalogen, C₁₋₅alkoxy, hydroxy, C₁₋₅ alkyl, cyano, nitro, R^(a)R^(b)N oris taken together with R²⁷.
 8. A compound of claim 7, wherein R¹ istaken together with R²⁷.
 9. A compound of claim 8, wherein R¹ and R²⁷taken together are selected from: a) —CH₂NR⁹—(C═O)— b) —OCH₂(C═O)— c)—CH₂CH₂(C═O)— d) —CH₂—O(C═O)— e) —CH₂S(C═O)— f) —O(C═O)— g) —CH₂(C═O)—h) —NR⁹(C═O)— i) —NR⁹(SO₂)— j) —CH₂NR⁹SO₂— k) —NR⁹CH₂(C═O)— and l)—SCH₂(C═O)—.
 10. A compound of claim 9, wherein R¹ and R²⁷ takentogether are selected from: a) —CH₂—(C═O)— b) —O(C═O)— c) —CH₂CH₂— d)—S(C═O)— e) —N═N— f) —NR⁹SO₂— g) —N═CR⁹— h) —NR⁹(C═O)— and i) —CH═CH—.11. A compound of claim 3, wherein R² is hydrogen, halogen, C₁₋₅ alkoxy,C₁₋₅ alkyl, cyano, or R^(e)R^(f)N, where R^(e) and R^(f) are H or C₁₋₅alkyl, or are taken together to form a 5-7 membered heterocyclic ring.12. A compound of claim 3, wherein R³ is hydrogen, halogen, C₁₋₅ alkoxy,C₁₋₅ alkyl, cyano, nitro, or R^(g)R^(h)N, where R^(e) and R^(f) are H orC₁₋₅ alkyl, or are taken together to form a 5-7 membered heterocyclicring.
 13. A compound of claim 1, wherein R⁵ and R⁶ are independentlyselected from hydrogen and C₁₋₃ alkyl.
 14. A compound of claim 12,wherein one of R⁵ and R⁶ is H.
 15. A compound of claim 14, wherein R⁵and R⁶ are each H.
 16. A compound of claim 1, wherein R⁸ is H and R⁷ is5-7 membered carbocyclyl or heterocyclyl.
 17. A compound of claim 1,wherein R⁷ and R⁸ are taken together to form an optionally substituted5- to 7-membered carbocyclic or heterocyclic ring.
 18. A compound ofclaim 16, wherein R⁷ and R⁸ taken together form a six-memberedheterocyclyl.
 19. A compound of claim 16, wherein R⁷ and R⁸ takentogether form pyridinyl, pyrimidinyl, or piperazinyl, optionallyN-substituted with —(C═O)R⁴, SO₂—R⁴, or —(C═O)NHR⁴.
 20. A compound ofclaim 3, wherein each of R^(a), R^(e), R^(m), and R^(o) is independentlyselected from hydrogen, C₁₋₅ alkyl, C₂₋₈ acyl, and the respective ROC═O,RRNC═O, RSO, RSO₂, and RRNSO₂ groups.
 21. A compound of claim 19,wherein each of R^(a), R^(e), R^(m), R^(o), R^(b), R^(f), R^(n), andR^(p) is independently selected from hydrogen and C₁₋₅ alkyl; or,independently, R^(a) and R^(b), R^(e) and R^(f), R^(m) and R^(n), andR^(o) and R^(p), taken together, form an optionally substituted 4- to7-membered carbocyclic or heterocyclic ring.
 22. A compound of claim 21,wherein: (1) R^(a) and R^(b) taken together are independentlymorpholinyl, piperidinyl, or pyrrolidinyl; (2) R^(e) and R^(f) takentogether are morpholinyl, piperidinyl, or pyrrolidinyl; or (3) both (1)and (2) apply.
 23. A compound of claim 3, wherein each of R^(c) andR^(d), R^(i) and R^(j), R^(k) and R^(l) is independently hydrogen orC₁₋₅ alkyl, alternatively, R^(c) and R^(d), R^(i) and R^(j), and R^(k)and R^(l), independently, can be taken together to form an optionallysubstituted 4- to 7-membered heterocyclic ring, which ring may besaturated, unsaturated or aromatic.
 24. A compound of claim 23, whereinR^(c) and R^(d), R^(i) and R^(j), and R^(k) and R^(l), independently,are taken together to form an optionally substituted 4- to 7-memberedheterocyclic ring, which ring may be saturated, unsaturated or aromatic.25. A compound of claim 3, wherein each of R^(b), R^(f), R^(n), R^(p),R³², R³³, R³⁴, R³⁵, R³⁶, R³⁷, R³⁹, and R⁴⁰ is independently H or C₁₋₅alkyl.
 26. A compound of claim 3, wherein each of R¹¹, R¹², R¹³, R¹⁴,R¹⁵, R¹⁶, R¹⁹, R³⁸, and R⁴¹ is independently H or C₁₋₅ alkyl.
 27. Acompound of claim 3, wherein R^(g) is C₁₋₅ alkyl, C₂₋₈ acyl, R¹⁷OC═O,R¹⁷R¹⁸NC═O, R¹⁶S, R¹⁶SO, R¹⁶SO₂, or R¹⁷R¹⁸NSO₂; and R^(h) hydrogen orC₁₋₅ alkyl; alternatively, R^(g) and R^(h) can be taken together to forman optionally substituted 4- to 7-membered heterocyclic ring.
 28. Acompound of claim 3, wherein R¹⁷ and R¹⁸ independently are hydrogen orC₁₋₅ alkyl.
 29. A compound of claim 1, wherein n is
 1. 30. A compound ofclaim 1, wherein n is
 0. 31. A compound of claim 1, wherein G is C₃₋₄alkanediyl, optionally substituted with hydroxy, halogen, (L)-C₁₋₅alkyloxy, or [(L)-C₁₋₅ alkylene]amino.
 32. A compound of claim 31,wherein G is C₃ alkanediyl, optionally substituted with hydroxy,(L)-C₁₋₅ alkyloxy, or [(L)-C₁₋₅ alkylene]amino.
 33. A compound of claim3, wherein each of R²⁰ and R²¹ is independently selected from hydrogen,halogen, C₁₋₅ alkoxy, C₁₋₅ alkyl, cyano, nitro, and R^(m)R^(n)N orR^(o)R^(p)N, respectively.
 34. A compound of claim 33, wherein each ofR²⁰ and R²¹ is independently selected from hydrogen, halogen, C₁₋₃alkyl, and R^(m)R^(n)N or R^(o)R^(p)N, respectively.
 35. A compound ofclaim 1, wherein Ar represents a monocyclic ring, optionally substitutedwith 1 to 2 substituents selected from halogen, C₁₋₅ alkyl, cyano,nitro, R²²R²³N, halomethyl, and halomethoxy.
 36. A compound of claim 35,wherein Ar is a six membered ring substituted with between 1 and 2substituents independently selected from methyl, halogen, CF₃, and OCF₃,said substituent or substituents being at the 4-position, or at the 3-and 4-positions, respectively.
 37. A compound of claim 1, wherein eachof R²², R²³, and R²⁴ is hydrogen or C₁₋₅ alkyl.
 38. A compound of claim1, wherein R²⁵ and R²⁶ independently are hydrogen or C₁₋₅ alkyl; or,alternatively, R²⁵ and R²⁶ can be taken together to form an optionallysubstituted 4- to 7-membered heterocyclic ring.
 39. A compound of claim38, wherein each of R²⁵ and R²⁶ is independently hydrogen or C₁₋₅ alkyl.40. A compound of claim 1, wherein W is NR²⁷.
 41. A compound of claim 1,wherein W is CHR²⁸, and R²⁸ is hydrogen or C₁₋₅ alkyl.
 42. A compound ofclaim 1, wherein R²⁹ is C₁₋₅ alkyl; or R³⁰ and R³¹ are independentlyselected from hydrogen and C₁₋₅ alkyl, or R³⁰ and R³¹ are taken togetherto form a 5-6 membered heterocyclyl.
 43. A compound of claim 3, whereinAr₂ is formula (e) and R¹ halogen, C₁₋₅ alkoxy, hydroxy, C₁₋₅ alkyl,cyano, nitro, and R^(a)R^(b)N, or R¹ can be taken together with R²⁷ asprovided below; R² is hydrogen, halogen, C₁₋₅ alkoxy, C₁₋₅ alkyl, orR^(e)R^(f)N; R³ is hydrogen, halogen, C₁₋₅ alkoxy, hydroxy, C₁₋₅ alkyl,cyano, R^(g)R^(h)N; R⁵ and R⁶ are independently selected from hydrogenand C₁₋₃ alkyl; R⁷ and R⁸ independently are taken together to form anoptionally substituted 5- to 7-membered carbocyclic or heterocyclicring, which ring may be saturated, unsaturated or aromatic; each ofR^(a,) R^(e), R^(m) , and R^(o) is independently selected from hydrogen,C₁₋₅ alkyl, C₂₋₈ acyl, and the respective ROC═O, RRNC═O, RS, RSO, RSO₂,and RRNSO₂ groups; each of R^(b), R^(f), R^(n), and R^(p), isindependently selected from hydrogen and C₁₋₅ alkyl; each of R¹¹, R¹²,R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁹, and R³⁸ is independently C₁₋₅ alkyl; each ofR^(c) and R^(d), R^(i) and R^(j), R^(k) and R^(l), R³² and R³³, R³⁴ andR³⁵, R³⁶ and R³⁷ are independently are hydrogen or C₁₋₅ alkyl, or aretaken together to form an optionally substituted 4- to 7-memberedheterocyclic ring; R^(g) is hydrogen, C₁₋₅ alkyl, C₂₋₈ acyl, R¹⁷OC═O,R¹⁷R¹⁸NC═O, R¹⁶S, R¹⁶SO, R¹⁶SO₂, or R¹⁷R¹⁸NSO₂; R^(h) is hydrogen orC₁₋₅ alkyl; alternatively, R^(g) and R^(h) can be taken together to forman optionally substituted 4- to 7-membered heterocyclic ring; R¹⁷ andR¹⁸ independently are hydrogen or C₁₋₅ alkyl; n is 0 or 1; G is C₃₋₄alkenediyl or C₃₋₄ alkanediyl, optionally substituted with hydroxy,halogen, C₁₋₅ alkyloxy, (L)-C₁₋₅ alkoxy, N₃, or [(L)-C₁₋₅alkylene]amino; L is amino, mono- or di-C₁₋₅ alkylamino, pyrrolidinyl,morpholinyl, piperidinyl homopiperidinyl, or piperazinyl, whereinavailable ring nitrogens may be optionally substituted with C₁₋₅ alkyl,benzyl, C₁₋₅ alkylcarbonyl, or C₁₋₅ alkyloxycarbonyl; Y_(e) is nitrogenor R²⁰C; Z_(e) is nitrogen or R²¹C R²⁰ and R²¹ are independentlyselected from hydrogen, halogen, C₁₅-alkoxy, C₁₋₅ alkyl, cyano, nitro,and R^(m)R^(n)N or R^(o)R^(p)N, respectively; alternatively, R³ and R²⁰or R³ and R²¹ can be taken together to form an optionally substituted 5-or 6-membered carbocyclic or heterocyclic ring; Ar represents amonocyclic or bicyclic aryl or heteroaryl ring, optionally substitutedwith between 1 and 3 substituents independently selected from halogen,C₁₋₅ alkoxy, C₁₋₅ alkyl, cyano, nitro, R²²R²³N, R²⁴SO₂, R²⁴OC═O,R²⁵R²⁶NC═O, CF₃, OCF₃, CF₃S, and C₁₋₅ alkylthio; R²² is hydrogen, C₁₋₅alkyl, phenyl, benzyl, phenethyl, C₁₋₅ heterocyclyl, C₂₋₈ acyl, aroyl,R²⁴OC═, R²⁵R²⁶NC═O, R²⁴SO, R²⁴SO₂, or R²⁵R²⁶NSO₂; R²³ is hydrogen orC₁₋₅alkyl; alternatively, R²² and R²³ can be taken together to form anoptionally substituted 4- to 7-membered heterocyclic ring; R²⁴ ishydrogen or C₁₋₅ alkyl; R²⁵ and R²⁶ are independently hydrogen or C₁₋₅alkyl; or, alternatively, R²⁵ and R²⁶ can be taken together to form anoptionally substituted 4- to 7-membered heterocyclic; W is NR²⁷or CHR²⁸;R²⁷ is hydrogen, C₁₋₅alkyl, R²⁹OC═O, R³⁰R³¹NC═O, R²⁹SO, R²⁹SO₂, orR³⁰R³¹NSO₂; or, alternatively, R²⁷ and R¹ can be taken together to forman optionally substituted 5- or 6-membered heterocyclic ring, which ringmay be saturated, unsaturated or aromatic; R²⁸ is hydrogen, hydroxy,C₁₋₅ heterocyclyl, phenyl, or C₁₋₅ alkyl; R²⁹ is C₁₋₅ alkyl; and R³⁰ andR³¹ are independently selected from hydrogen, C₁₋₅ alkyl; alternatively,R³⁰ and R³¹ can be taken together to form an optionally substituted 4-to 7-membered heterocyclic.
 44. A compound of claim 42, wherein R¹ andR²⁷ taken together are selected from: a) —CH₂NR⁹—(C═O)— b) —OCH₂(C═O)—c) —CH₂CH₂(C═O)— d) —CH₂—O(C═O)— e) —CH₂S(C═O)— f) —O(C═O)— g)—CH₂(C═O)— h) —NR⁹(C═O)— i) —NR⁹(SO₂)— j) —CH₂NR⁹SO₂— k) —NR⁹CH₂(C═O)—and l) —SCH₂(C═O)—.
 45. A compound of claim 42, wherein R¹ takentogether with R₂₇ are selected from: a) —CH₂—(C═O)— b) —O(C═O)— c)—CH₂CH₂— d) —S(C═O)— e) —N═N— f) —NR⁹SO₂— g) —N═CR⁹— h) —NR⁹(C═O)— andi) —CH═CH—.
 46. A compound of claim 1, wherein one of R⁵ and R⁶ is H, R⁷and R⁸ are taken together to form an optionally substituted 6-memberedcarbocyclic or heterocyclic ring; and Ar represents a monocyclic ring,optionally substituted with 1 to 2 substituents selected from halogen,C₁₋₅ alkyl, cyano, nitro, R²²R²³N, CF₃ and OCF₃.
 47. A compound of claim46, wherein both R⁵ and R⁶ are each H, and Ar is a six membered ringsubstituted with between 1 and 2 substituents independently selectedfrom halogen, methyl, CF₃, and OCF₃, said substituent or substituentsbeing at the 4-position, or at the 3- and 4-positions.
 48. A compound ofclaim 47, wherein R⁷ and R⁸ taken together form tetrahydropyridinyl,optionally N-substituted with —(C═O)R⁴, SO₂—R⁴, or —(C═O)NHR⁴.
 49. Acompound of claim 5, wherein X_(f) is C═O, SO₂, or CHR^(1f), and Y_(f)is O or NR^(2f), where R^(2f) is H, C₁₋₅ alkyl, C₂₋₅ heterocyclyl, C₁₋₅cyanoalkyl, or (C₁₋₅ alkoxycarbonyl)C₁₋₅ alkylene.
 50. A compound ofclaim 49, wherein R^(2f) is H, C₁₋₃ alkyl, or a C₂₋₅ heterocyclyl.
 51. Acompound of claim 5, wherein X_(f) is C═O, and Y_(f) is O, CHR^(2f) orNR^(2f), where R^(2f) is H, C₁₋₅ alkyl, C₂₋₅ heterocyclyl, C₁₅cyanoalkyl, or (C₁₋₅ alkoxycarbonyl)C₁₋₅ alkylene.
 52. A compound ofclaim 51, wherein X_(f) is C═O and Y_(f) is O.
 53. A compound of claim5, wherein m is 0 and p is 0; m is 0 and p is 1; or m is 1 and p is 0.54. A compound of claim 53, wherein p is
 0. 55. A compound of claim 1,wherein R^(z) is H.
 56. A compound of claim 1, wherein R^(z) is OH. 57.A compound of claim 1, wherein R^(z) is absent.
 58. A compound of claim3, wherein R²⁰ and R³ taken together are a six-membered carbocyclic orheterocyclic ring optionally substituted with between 1 and 3substituents independently selected from halo, C₁₋₃ alkoxy, di(C₁₋₃alkyl)amino, and C₂₋₅ acyl.
 59. A compound of claim 3, wherein each ofR²⁰ and R³ is H.
 60. (canceled)
 61. (canceled)
 62. (canceled) 63.(canceled)
 64. (canceled)
 65. (canceled)
 66. (canceled)
 67. (canceled)68. (canceled)
 69. (canceled)
 70. (canceled)
 71. A pharmaceuticalcomposition, comprising a compound of claim 1, 3, or 5, and apharmaceutically acceptable carrier.
 72. A method for treating a subjectwith a condition mediated by cathepsin S, said method comprisingadministering to the subject a therapeutically effective amount of apharmaceutical composition comprising a compound of claim 1, 3, or 5.73. A method for inhibiting cathepsin S activity in a subject, saidmethod comprising administering to the subject a therapeuticallyeffective amount of a pharmaceutical composition comprising a compoundof claim 1, or
 3. 74. A method for treating an autoimmune disease, orinhibiting the progression of an autoimmune disease, in a subject, saidmethod comprising administering to the subject a therapeuticallyeffective amount of a pharmaceutical composition comprising a compoundof claim 1, or
 3. 75. A method of claim 74, wherein the autoimmunedisease is selected from lupus, rheumatoid arthritis, and asthma.
 76. Amethod of claim 74, wherein the autoimmune disease is asthma.
 77. Amethod for treating or inhibiting the progression of tissue transplantrejection in a subject, said method comprising administering to thesubject a therapeutically effective amount of a pharmaceuticalcomposition comprising a compound of claim 1, or
 3. 78. A method ofclaim 77, wherein said administration occurs after said subject hasundergone a tissue transplant procedure.
 79. A method of claim 77,wherein said administration to said subject occurs before or during atissue transplant procedure.